U.S. patent number 11,066,442 [Application Number 16/526,862] was granted by the patent office on 2021-07-20 for deuterated compounds, compositions, and methods for treating cancers associated with etbr activation.
This patent grant is currently assigned to ENB Therapeutics, Inc.. The grantee listed for this patent is ENB Therapeutics, Inc.. Invention is credited to Sumayah Jamal.
United States Patent |
11,066,442 |
Jamal |
July 20, 2021 |
**Please see images for:
( Certificate of Correction ) ** |
Deuterated compounds, compositions, and methods for treating
cancers associated with ETBR activation
Abstract
Disclosed herein are deuterated compounds, pharmaceutical
compositions thereof, and methods for treating ETBR-related
cancers. Also disclosed herein is a delivery system for the
controlled, systemic release of at least one deuterated ETBR
antagonist, optionally in conjunction with an additional
anti-oncologic agent.
Inventors: |
Jamal; Sumayah (New York,
NY) |
Applicant: |
Name |
City |
State |
Country |
Type |
ENB Therapeutics, Inc. |
New York |
NE |
US |
|
|
Assignee: |
ENB Therapeutics, Inc. (New
York, NY)
|
Family
ID: |
67212721 |
Appl.
No.: |
16/526,862 |
Filed: |
July 30, 2019 |
Prior Publication Data
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Document
Identifier |
Publication Date |
|
US 20190345197 A1 |
Nov 14, 2019 |
|
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
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16246398 |
Jan 11, 2019 |
10435434 |
|
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62616729 |
Jan 12, 2018 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07B
59/002 (20130101); A61P 35/00 (20180101); A61K
38/177 (20130101); C07K 5/0808 (20130101); C07K
5/02 (20130101); C07B 2200/05 (20130101) |
Current International
Class: |
C07K
5/02 (20060101); A61K 38/17 (20060101); A61P
35/00 (20060101); C07K 5/083 (20060101); C07B
59/00 (20060101) |
References Cited
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2013127004 |
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Sep 2013 |
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WO |
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2014025837 |
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Feb 2014 |
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WO |
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2016196381 |
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Dec 2016 |
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WO |
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WO-2017024032 |
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Feb 2017 |
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WO |
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Jan 2021 |
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WO |
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|
Primary Examiner: Harward; Soren
Assistant Examiner: Lee; Jia-Hai
Attorney, Agent or Firm: Goodwin Procter LLP
Parent Case Text
CROSS-REFERENCE
This application is a continuation of U.S. application Ser. No.
16/246,398, filed Jan. 11, 2019, which claims the benefit of U.S.
Provisional Application No. 62/616,729, filed Jan. 12, 2018, which
is incorporated herein by reference in its entirety.
Claims
What is claimed is:
1. A method of treating a tumor in a subject in need thereof,
comprising administering to the subject a deuterated endothelin
B-receptor (ETBR) antagonist according to Formula: ##STR00025## a
stereoisomer, or a pharmaceutically acceptable salt thereof.
2. The method of claim 1, wherein administration of the ETBR
antagonist induces the growth and/or formation of a tertiary
lymphoid organ (TLO) in the tumor.
3. The method of claim 1, wherein administration of the ETBR
antagonist increases Tumor Infiltrating Lymphocyte (TIL)
infiltration of the tumor.
4. The method of claim 1, wherein immune cell infiltration of the
tumor is increased.
5. The method of claim 1, wherein the volume and/or mass of the
tumor is reduced.
6. The method of claim 1, further comprising administering to the
subject a checkpoint inhibitor.
7. The method of claim 6, wherein the checkpoint inhibitor is a PD1
inhibitor.
8. The method of claim 7, wherein the PD1 inhibitor is an anti-PD1
antibody.
9. The method of claim 8, wherein an anti-PD1 antibody is
pidilizumab, BMS-936559, nivolumab, pembrolizumab or any
combination thereof.
10. The method of claim 7, wherein the deuterated analog and the
anti-PD1 inhibitor are administered at different times.
11. The method of claim 7, wherein the ETBR antagonist according to
Formula (1) is administered 2, 3, 4, or 5 times frequently as the
anti-PD1 inhibitor.
12. The method of claim 11, wherein the ETBR antagonist according
to Formula (1) is administered 3 times as frequently as the
anti-PD1 antibody.
Description
SEQUENCE LISTING
The instant application contains a Sequence Listing which has been
submitted electronically in ASCII format and is hereby incorporated
by reference in its entirety. Said ASCII copy, created on Jan. 11,
2019, is named "55520704301_SL.txt" and is 784 bytes in size.
BRIEF SUMMARY
Disclosed herein are compounds. In some embodiments, a compound can
be a compound of Formula (1):
##STR00001## a stereoisomer thereof, or a pharmaceutically
acceptable salt thereof, where: n can be an integer from 0-5; m can
be an integer from 0-3; X can be a positively charged counterion;
R.sub.1 and R.sub.3 can be independently --H, -D, --CH.sub.3,
--CH.sub.2D, --CHD.sub.2, or --CD.sub.3; R.sub.2a, R.sub.2b,
R.sub.4, R.sub.5, and R.sub.6 can be independently --CH.sub.3,
--CH.sub.2D, --CHD.sub.2, or --CD.sub.3; and at least one of
R.sub.1, R.sub.2, or R.sub.3 comprises deuterium. In some
embodiments, m can be 0, n can be 0, and R.sub.2a and R.sub.2b can
be --CH.sub.2D. In some embodiments, a compound can be a compound
of Formula (2):
##STR00002## or a pharmaceutically acceptable salt thereof. In some
embodiments, a compound can be a compound of Formula (3):
##STR00003## or a pharmaceutically acceptable salt thereof. In some
embodiments, a compound can be a compound of Formula (4):
##STR00004## or a pharmaceutically acceptable salt thereof. In some
embodiments, a compound can be a compound of Formula (5):
##STR00005## or a pharmaceutically acceptable salt thereof. In some
embodiments, a compound can be a compound of Formula 6:
##STR00006## In some embodiments, n can be 0 or 1. In some
embodiments, n can be 1, R.sub.1 can be -D; and R.sub.2a and
R.sub.2b can be --CH.sub.3. In some embodiments, n can be 0,
R.sub.1 can be --H; R.sub.2a can be --CH.sub.3 and R.sub.2b can be
--CH.sub.2D. In some embodiments, n can be 0, R.sub.1 can be --H;
R.sub.2a can be --CH.sub.2D and R.sub.2b can be --CH.sub.3. In some
embodiments, n can be 0, R.sub.1 can be --H; and R.sub.2a and
R.sub.2b can be --CH.sub.2D. In some embodiments, n can be 1,
R.sub.1 can be -D; and R.sub.2a and R.sub.2b can be
--CH.sub.2D.
Also disclosed herein are compounds or pharmaceutically acceptable
salts thereof selected from the group consisting of:
##STR00007##
Also disclosed herein are pharmaceutical composition that comprises
a compound as described herein and a pharmaceutically acceptable
excipient, diluent, or carrier. In some embodiments, a
pharmaceutical composition comprises a pharmaceutically acceptable
carrier. In some embodiments, a pharmaceutically acceptable carrier
can be dimethyl sulfoxide (DMSO). In some embodiments, the compound
is:
##STR00008##
Also disclosed herein are methods of treating cancer that comprises
administering to a subject in need thereof a pharmaceutical
composition as described herein. In some embodiments, a method can
further comprise administering an immune checkpoint inhibitor to
the subject. In some embodiments, an immune checkpoint inhibitor
can be an anti-PD1 antibody.
Also disclosed herein are methods of treating cancer in a subject
in need thereof, that comprises administering to the subject a
compound as described herein, wherein the compound can be in an
amount effective for treating or ameliorating at least one symptom
of the cancer in the subject. In some embodiments, a method can
further comprise administering to the subject at least one immune
checkpoint inhibitor to the subject. In some embodiments, the at
least one immune checkpoint inhibitor comprises at least one
anti-PD1 antibody, at least one anti-PD-L1 antibody, at least one
anti-CTLA4 antibody, or any combination thereof. In some
embodiments, the at least one anti-PD1 antibody comprises
pidilizumab, BMS-936559, nivolumab, pembrolizumab or any
combination thereof. In some embodiments, the at least one
anti-PD-L1 antibody comprises atezolizumab, avelumab, durvalumab,
MDX-1105, or any combination thereof. In some embodiments, the
cancer can be a solid tumor cancer, malignant melanoma, metastatic
melanoma, malignant squamous cell carcinoma, metastatic squamous
cell carcinoma, glioblastoma, brain cancer, pancreatic cancer,
colon cancer, breast cancer, ovarian cancer, prostate cancer, or
any combination thereof. In some embodiments, the compound and the
immune checkpoint inhibitor can be administered at different times.
In some embodiments, the compound can be administered 2, 3, 4, or 5
times frequently as the immune checkpoint inhibitor. In some
embodiments, the compound can be administered 3 times frequently as
the immune checkpoint inhibitor. In some embodiments, the compound
can be administered 3 times every 2-3 weeks and the immune
checkpoint inhibitor can be administered 1 time the every 2-3
weeks. In some embodiments, the compound can be administered 3
times about every 21 days and the immune checkpoint inhibitor can
be administered 1 time the about every 21 days. In some
embodiments, the subject can be a human. In some embodiments, the
subject can be resistant to an immunotherapy before the treatment.
In some embodiments, the administration results in at least one of
improved biologic activity, increased stability, prolonged serum
bioavailability, prolonged ETBR target engagement, or any
combination thereof, compared to a non-deuterated parent compound,
as determined by measuring a serum ET-1 level. In some embodiments,
the administration restores Tumor Infiltrating Lymphocytes (TILs),
intratumoral tertiary lymphoid organ (TLO) formation, or a
combination thereof, in a tumor microenvironment.
Also disclosed herein are methods of forming a tertiary lymphoid
organ (TLO) within a tumor in a subject in need thereof, that
comprises administering to the subject a compound as described
herein, whereby the tumor can be reduced or eradicated. In some
embodiments, the compound is
##STR00009## a stereoisomer thereof, or a pharmaceutically
acceptable salt thereof. In some embodiments, the compound can be
in a pharmaceutically acceptable excipient that comprises dimethyl
sulfoxide (DMSO).
Also disclosed herein are compounds of Formula (7):
##STR00010## a stereoisomer thereof, or a pharmaceutically
acceptable salt thereof, where: R.sup.1, R.sup.2, R.sup.3, R.sup.4,
or R.sup.5 can be independently hydrogen, halogen, hydroxyl,
deuterium, halogen, hydroxy, amino, nitro, optionally substituted
C.sub.1-C.sub.8 alkyl, optionally substituted C.sub.2-C.sub.8
alkenyl, optionally substituted C.sub.2-C.sub.8 alkynyl, optionally
substituted C.sub.3-C.sub.8 cycloalkyl, optionally substituted
C.sub.1-C.sub.8 alkoxy, optionally substituted C.sub.1-C.sub.8
haloalkyl, optionally substituted aryl, or optionally substituted
heteroaryl, optionally wherein one or more of the carbons in the
piperidinyl ring can be a heteroatom selected from O, N, or S, or
wherein the piperidinyl ring may contain one or more double bonds;
R.sup.6 can be optionally substituted C.sub.1-C.sub.8 alkyl,
optionally substituted C.sub.2-C.sub.8 alkenyl, optionally
substituted C.sub.2-C.sub.8 alkynyl, optionally substituted
C.sub.3-C.sub.8-cycloalkyl, optionally substituted C.sub.1-C.sub.8
alkoxy, optionally substituted C.sub.1-C.sub.8 haloalkyl,
optionally substituted aryl, or optionally substituted heteroaryl,
wherein R.sup.6 optionally comprises deuterium; R.sup.7 can be
optionally substituted cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted aryl, optionally
substituted heteroaryl, optionally substituted polycyclic ring
system, optionally substituted bicyclic, optionally substituted
heterobicyclic, wherein R.sup.7 optionally comprises deuterium;
R.sup.8 and R.sup.9 can be independently optionally substituted
C.sub.1-C.sub.8 alkyl, optionally substituted C.sub.2-C.sub.8
alkenyl, optionally substituted C.sub.2-C.sub.8 alkynyl, optionally
substituted C.sub.3-C.sub.8 cycloalkyl, optionally substituted
C.sub.1-C.sub.8 alkoxy, optionally substituted C.sub.1-C.sub.8
haloalkyl, optionally substituted aryl, optionally substituted
heteroaryl, or --COOR', or R.sup.8 and R.sup.9 may be taken
together to form a optionally substituted cycloalkyl, optionally
substituted cycloalkyl heterocycloalkyl, optionally substituted
aryl, optionally substituted heteroaryl, or optionally substituted
polycyclic ring system, wherein R.sup.8 or R.sup.9 each optionally
comprises deuterium; R' can be hydrogen, hydroxy, or
C.sub.1-C.sub.8 alkyl; and wherein at least one of R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, or
R.sup.9 comprises deuterium. In some embodiments, two of R.sup.1,
R.sup.2, R.sup.3, R.sup.4, or R.sup.5 comprise deuterium. Also
disclosed herein are pharmaceutical compositions that comprise an
effective amount of the compound, and a pharmaceutically acceptable
carrier. In some embodiments, the pharmaceutically acceptable
carrier can be dimethyl sulfoxide (DMSO). Also disclosed herein are
methods of treating cancer in a subject in need thereof, that
comprises administering to the subject the compound the
pharmaceutical composition, wherein the method can be effective in
treating or ameliorating at least one symptom of the cancer in the
subject. In some embodiments, the method can further comprise
administering to the subject at least one additional anti-oncologic
therapeutic agent. In some embodiments, the at least one additional
anti-oncologic agent comprises a bRAF inhibitor, an immune
checkpoint inhibitor, a caspase-8 inhibitor, an ETAR antagonist,
niacinamide, a chemotherapeutic agent, or any combination thereof.
In some embodiments, the at least one additional anti-oncologic
agent comprises at least one of the immune checkpoint inhibitor. In
some embodiments, the at least one immune checkpoint inhibitor
comprises at least one anti-PD1 antibody, at least one anti-PD-L1
antibody, at least one anti-CTLA4 antibody, or any combination
thereof. In some embodiments, the at least one anti-PD1 antibody
comprises pidilizumab, BMS-936559, nivolumab, pembrolizumab or any
combination thereof. In some embodiments, the at least one
anti-PD-L1 antibody comprises atezolizumab, avelumab, durvalumab,
MDX-1105, or any combination thereof. In some embodiments, the
cancer can be a solid tumor cancer, malignant melanoma, metastatic
melanoma, malignant squamous cell carcinoma, metastatic squamous
cell carcinoma, glioblastoma, brain cancer, pancreatic cancer,
colon cancer, breast cancer, ovarian cancer, prostate cancer, or
any combination thereof. In some embodiments, the compound and the
at least one additional anti-oncologic agent can be administered at
different times. In some embodiments, the compound can be
administered 2, 3, 4, or 5 times frequently as the immune
checkpoint inhibitor. In some embodiments, the compound can be
administered 3 times frequently as the immune checkpoint inhibitor.
In some embodiments, the compound can be administered 3 times every
2-3 weeks and the immune checkpoint inhibitor can be administered 1
time the every 2-3 weeks. In some embodiments, the compound can be
administered 3 times about every 21 days and the immune checkpoint
inhibitor can be administered 1 time the about every 21 days. In
some embodiments, the subject can be a human. In some embodiments,
the subject can be resistant to an immunotherapy before the
treatment. In some embodiments, the administration results in at
least one of improved biologic activity, increased stability,
prolonged serum bioavailability, prolonged ETBR target engagement,
or any combination thereof, compared to a non-deuterated parent
compound, as determined by measuring a serum ET-1 level. In some
embodiments, the administration restores Tumor Infiltrating
Lymphocytes (TILs), intratumoral tertiary lymphoid organ (TLO)
formation, or a combination thereof, in a tumor
microenvironment.
Also disclosed herein are compounds of Formula (8):
##STR00011## a stereoisomer thereof, or a pharmaceutically
acceptable salt thereof, where: R.sup.2, R.sup.3, or R.sup.4 can be
independently hydrogen, deuterium, halogen, hydroxy, amino, nitro,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.8 alkoxy,
C.sub.1-C.sub.8 haloalkyl, aryl, or heteroaryl; R.sup.6 can be
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.8 alkoxy,
C.sub.1-C.sub.8 haloalkyl, aryl, or heteroaryl, wherein R.sup.6
optionally comprises deuterium; R.sup.7 can be substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, or a substituted or unsubstituted
polycyclic ring system, wherein R.sup.7 optionally comprises
deuterium; R.sup.8 and R.sup.9 can be independently C.sub.1-C.sub.8
alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl,
C.sub.3-C.sub.8-cycloalkyl, C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8
haloalkyl, aryl, heteroaryl, or --COOR', or R.sup.8 and R.sup.9 may
be taken together to form a substituted or unsubstituted
cycloalkyl, substituted or unsubstituted cycloalkyl
heterocycloalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, or substituted or unsubstituted
polycyclic ring system, wherein R.sup.8 or R.sup.9 each optionally
comprises deuterium; R' can be hydrogen, hydroxy, or
C.sub.1-C.sub.5 alkyl; and wherein at least one of R.sup.1,
R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, or
R.sup.9 comprises deuterium. In some embodiments, two of R.sup.1,
R.sup.2, R.sup.3, R.sup.4, or R.sup.5 comprise deuterium. Also
disclosed herein are pharmaceutical compositions that comprise an
effective amount of the compound, and a pharmaceutically acceptable
carrier. In some embodiments, the pharmaceutically acceptable
carrier can be dimethyl sulfoxide (DMSO). Also disclosed herein are
methods of treating cancer in a subject in need thereof, that
comprises administering to the subject the compound the
pharmaceutical composition, wherein the method can be effective in
treating or ameliorating at least one symptom of the cancer in the
subject. In some embodiments, the method can further comprise
administering to the subject at least one additional anti-oncologic
therapeutic agent. In some embodiments, the at least one additional
anti-oncologic agent comprises a bRAF inhibitor, an immune
checkpoint inhibitor, a caspase-8 inhibitor, an ETAR antagonist,
niacinamide, a chemotherapeutic agent, or any combination thereof.
In some embodiments, the at least one additional anti-oncologic
agent comprises at least one of the immune checkpoint inhibitor. In
some embodiments, the at least one immune checkpoint inhibitor
comprises at least one anti-PD1 antibody, at least one anti-PD-L1
antibody, at least one anti-CTLA4 antibody, or any combination
thereof. In some embodiments, the at least one anti-PD1 antibody
comprises pidilizumab, BMS-936559, nivolumab, pembrolizumab or any
combination thereof. In some embodiments, the at least one
anti-PD-L1 antibody comprises atezolizumab, avelumab, durvalumab,
MDX-1105, or any combination thereof. In some embodiments, the
cancer can be a solid tumor cancer, malignant melanoma, metastatic
melanoma, malignant squamous cell carcinoma, metastatic squamous
cell carcinoma, glioblastoma, brain cancer, pancreatic cancer,
colon cancer, breast cancer, ovarian cancer, prostate cancer, or
any combination thereof. In some embodiments, the compound and the
at least one additional anti-oncologic agent can be administered at
different times. In some embodiments, the compound can be
administered 2, 3, 4, or 5 times frequently as the immune
checkpoint inhibitor. In some embodiments, the compound can be
administered 3 times frequently as the immune checkpoint inhibitor.
In some embodiments, the compound can be administered 3 times every
2-3 weeks and the immune checkpoint inhibitor can be administered 1
time the every 2-3 weeks. In some embodiments, the compound can be
administered 3 times about every 21 days and the immune checkpoint
inhibitor can be administered 1 time the about every 21 days. In
some embodiments, the subject can be a human. In some embodiments,
the subject can be resistant to an immunotherapy before the
treatment. In some embodiments, the administration results in at
least one of improved biologic activity, increased stability,
prolonged serum bioavailability, prolonged ETBR target engagement,
or any combination thereof, compared to a non-deuterated parent
compound, as determined by measuring a serum ET-1 level. In some
embodiments, the administration restores Tumor Infiltrating
Lymphocytes (TILs), intratumoral tertiary lymphoid organ (TLO)
formation, or a combination thereof, in a tumor
microenvironment.
Also disclosed herein are compounds of Formula (9):
##STR00012## a stereoisomer thereof, or a pharmaceutically
acceptable salt thereof, where: R.sup.1 R.sup.2, R.sup.3, R.sup.4,
or R.sup.5 can be independently hydrogen, deuterium, halogen,
hydroxy, amino, nitro, C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.8 cycloalkyl,
C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8 haloalkyl, aryl, or
heteroaryl; R.sup.6 can be C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.8-cycloalkyl,
C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8 haloalkyl, aryl, or
heteroaryl, wherein R.sup.6 optionally comprises deuterium; R.sup.8
and R.sup.9 can be independently C.sub.1-C.sub.8 alkyl,
C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.8
cycloalkyl, R.sup.8 and R.sup.9 can be independently
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.8-cycloalkyl, C.sub.1-C.sub.8 alkoxy,
C.sub.1-C.sub.8 haloalkyl, aryl, heteroaryl, or --COOR', or R.sup.8
and R.sup.9 may be taken together to form a substituted or
unsubstituted cycloalkyl, substituted or unsubstituted cycloalkyl
heterocycloalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, or substituted or unsubstituted
polycyclic ring system, wherein R.sup.8 or R.sup.9 each optionally
comprises deuterium; R.sup.10 and R.sup.10' can be independently
hydrogen, deuterium, halogen, hydroxy, amino, nitro,
C.sub.1-C.sub.8alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.8-cycloalkyl, C.sub.1-C.sub.8 alkoxy,
C.sub.1-C.sub.8 haloalkyl, aryl, or heteroaryl; n can be an integer
from 0-4; and wherein at least one of R.sup.1, R.sup.2, R.sup.3,
R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10 or
R.sup.10' comprises deuterium. In some embodiments, n can be 0 and
both R.sup.10 and R.sup.10' can be hydrogen. In some embodiments,
two of R.sup.1, R.sup.2, R.sup.3, R.sup.4, or R.sup.5 comprise
deuterium. Also disclosed herein are pharmaceutical compositions
that comprise an effective amount of the compound, and a
pharmaceutically acceptable carrier. In some embodiments, the
pharmaceutically acceptable carrier can be dimethyl sulfoxide
(DMSO). Also disclosed herein are methods of treating cancer in a
subject in need thereof, that comprises administering to the
subject the compound the pharmaceutical composition, wherein the
method can be effective in treating or ameliorating at least one
symptom of the cancer in the subject. In some embodiments, the
method can further comprise administering to the subject at least
one additional anti-oncologic therapeutic agent. In some
embodiments, the at least one additional anti-oncologic agent
comprises a bRAF inhibitor, an immune checkpoint inhibitor, a
caspase-8 inhibitor, an ETAR antagonist, niacinamide, a
chemotherapeutic agent, or any combination thereof. In some
embodiments, the at least one additional anti-oncologic agent
comprises at least one of the immune checkpoint inhibitor. In some
embodiments, the at least one immune checkpoint inhibitor comprises
at least one anti-PD1 antibody, at least one anti-PD-L1 antibody,
at least one anti-CTLA4 antibody, or any combination thereof. In
some embodiments, the at least one anti-PD1 antibody comprises
pidilizumab, BMS-936559, nivolumab, pembrolizumab or any
combination thereof. In some embodiments, the at least one
anti-PD-L1 antibody comprises atezolizumab, avelumab, durvalumab,
MDX-1105, or any combination thereof. In some embodiments, the
cancer can be a solid tumor cancer, malignant melanoma, metastatic
melanoma, malignant squamous cell carcinoma, metastatic squamous
cell carcinoma, glioblastoma, brain cancer, pancreatic cancer,
colon cancer, breast cancer, ovarian cancer, prostate cancer, or
any combination thereof. In some embodiments, the compound and the
at least one additional anti-oncologic agent can be administered at
different times. In some embodiments, the compound can be
administered 2, 3, 4, or 5 times frequently as the immune
checkpoint inhibitor. In some embodiments, the compound can be
administered 3 times frequently as the immune checkpoint inhibitor.
In some embodiments, the compound can be administered 3 times every
2-3 weeks and the immune checkpoint inhibitor can be administered 1
time the every 2-3 weeks. In some embodiments, the compound can be
administered 3 times about every 21 days and the immune checkpoint
inhibitor can be administered 1 time the about every 21 days. In
some embodiments, the subject can be a human. In some embodiments,
the subject can be resistant to an immunotherapy before the
treatment. In some embodiments, the administration results in at
least one of improved biologic activity, increased stability,
prolonged serum bioavailability, prolonged ETBR target engagement,
or any combination thereof, compared to a non-deuterated parent
compound, as determined by measuring a serum ET-1 level. In some
embodiments, the administration restores Tumor Infiltrating
Lymphocytes (TILs), intratumoral tertiary lymphoid organ (TLO)
formation, or a combination thereof, in a tumor
microenvironment.
BRIEF DESCRIPTION OF THE DRAWINGS
The accompanying drawings, which are incorporated into and form a
part of the specification, illustrate several embodiments of the
present invention and, together with the description, serve to
explain the principles of the invention. The drawings are only for
the purpose of illustrating an embodiment of the invention and are
not to be construed as limiting the invention. Further objects,
features and advantages of the invention will become apparent from
the following detailed description taken in conjunction with the
accompanying figures showing illustrative embodiments of the
invention, in which:
FIG. 1 shows endothelin B receptor (ETBR) cell signal pathway. ETBR
is a seven transmembrane G-protein coupled receptor (GPCR).
Endothelin-1 (ET-1) is the ligand for the ETBR. Binding of ET-1 to
the receptor results in the activation of a number of downstream
kinases, including PTK, RAF, MEK, MAPK/ERK.
FIG. 2 shows drug resistance to bRAF inhibitors is due to ETBR
upregulation. Upregulation of ETBR allows melanoma cells to bypass
the block to MAPK/ERK activation. ETBR antagonists, including
specifically deuterated ETBR antagonists as described herein, block
ET-1 binding.
FIG. 3 shows that ET-1 is expressed by advanced melanomas. ET-1 is
the ligand that activates the ETBR, which causes melanoma cells to
proliferate, metastasize, and generate their own blood supply. The
tissue section is from a human invasive melanoma specimen stained
with an ET-1 specific label. The photograph indicates that the
melanoma is positive for ET-1. Invasive and metastatic melanomas
produce ET-1.
FIGS. 4A and 4B show determination of CXCR4 (h) inhibitory effect
for, A) BQ-788 and B) BQ-788-B, a specifically deuterated ETRB
antagonist (i.e., "Compound 1"). Cellular agonist effect was
calculated as a % of control response to a known reference agonist
for CXCR4 (h), and cellular antagonist effect was calculated as a %
inhibition of control reference agonist response for CXCR4. Results
showing .gtoreq.50% inhibition of agonist effect are considered
significant while those showing less than 25% inhibition are not
considered significant. The IC50 for BQ-788 was greater than about
1.0E-6 M. The IC50 for BQ-788-B was not calculable.
FIGS. 5A and 5B show determination of ETA (h) inhibitory effect for
A) BQ-788 and B) BQ-788-B, a specifically deuterated ETRB
antagonist. Cellular agonist effect was calculated as a % of
control response to a known reference agonist for ETA (h), and
cellular antagonist effect was calculated as a % inhibition of
control reference agonist response for ETA. Results showing
.gtoreq.50% inhibition of agonist effect are considered significant
while those showing less than 25% inhibition are not considered
significant. The IC50 for BQ-788 and BQ-788-B was not calculable
(i.e., the dose-response curve shows less than 25% effect at the
highest validated testing concentration).
FIG. 6 shows that specifically deuterated ETRB antagonists inhibit
melanoma growth and metastasis and induction of apoptosis in
melanoma tumor cells. Cellular agonist effect was calculated as a %
of control response to a known reference agonist for ETB (h), and
cellular antagonist effect was calculated as a % inhibition of
control reference agonist response for ETB. Results showing
.gtoreq.50% inhibition of agonist effect are considered significant
while those showing less than 25% inhibition are not considered
significant. The IC50 for BQ-788 was 5.1E-08 M and the Kd was
1.3E-08; while the IC50 for the specifically deuterated compound is
9.6E-08 M and a Kd of 2.5E-08.
FIG. 7 shows that BQ-788-B, a specifically deuterated ETRB
antagonist demonstrates enhanced biological activity relative to
BQ-788. BQ-788-B demonstrates a prolonged peak out to about 3 hours
as compared to BQ-788, which demonstrates a transient peak at about
30 minutes. The IC50 for BQ-788-B is 9.6E-08 M (MW=665.37). The
IC50 for BQ-788 is 5.6E-08 (MW=663.78).
FIG. 8 shows that a dual combination of specifically deuterated
ETRB antagonists and an immunotherapeutic results in superior
efficacy relative to current standard drug combinations. The
syngeneic melanoma model V600E+(BRAF mutated) SM1 tumor model was
used in C57BL/6 mice to assess efficacy of the specific deuterated
ETRB antagonist in combination with the immunotherapeutic ("B+P")
as compared to a standard of treatment, dabrafenib with anti-PD1
("D+P").
FIG. 9 shows that a dual combination of the specifically deuterated
ETRB antagonist BQ-788-B and immunocheckpoint inhibitors (e.g.
anti-PD1) eradicates tumors. Histological examination of V600E+
melanoma tumor cells implanted into C57BL/6 mice 21 days after
treatment as indicated in FIG. 8. BQ-788-B and immunocheckpoint
inhibitors in combination eradicated the tumors in 21 days,
promoted robust infiltration by CD8+ lymphocytes (TILs), and
induced tertiary lymphoid organ (TLO) formation.
FIG. 10 shows intratumoral TLO formation induced by combination
therapy including the immunocheckpoint inhibitor anti-PD1 and the
specifically deuterated ETRB antagonist BQ-788-B. Histological
examination of V600E+ melanoma tumor cells implanted into C57BL/6
mice 21 days after treatment as indicated in FIG. 8 with BQ-788-B
and anti-PD1 combination therapy. The staining of CD8+, CD4+ and
Treg (FoxP3) lymphocytes indicates that the combination therapy
promotes strong mobilization of lymphocytes to the tumor, which is
associated with tumor eradication and positive patient
outcomes.
FIG. 11 shows intratumoral (internal) TLO formation associated with
treatment with the specifically deuterated compound BQ-788-B. The
tables summarize results obtained with combination therapies (two-
and three-part), TLO formation and efficacy for tumor eradication.
The data indicate that (i) internal TLO formation is associated
with tumor reduction; and (ii) the combination immunocheckpoint
inhibitors and BQ-788-B was most frequently associated with
intratumoral TLO formation and tumor reduction.
FIG. 12 shows that the inclusion of the specifically deuterated
ETRB antagonist BQ-788-B with the immunocheckpoint inhibitor
anti-PD1 restores sensitivity to anti-PD1. The addition of
dabrafenib to anti-PD1/BQ-788-B combination impairs efficacy,
possibly due to dabrafenib's ability to increase Tregs and
tumor-associated macrophages (TAMs).
FIG. 13 shows that specifically deuterated compound BQ-788-B at 0.6
.mu.g in combination with immunocheckpoint inhibitor (e.g.
anti-CTLA, anti-PD-L1, or anti-PD1) and dabrafenib promotes diffuse
CD8+ TIL staining. Histological examination of V600E+ melanoma
tumor cells implanted into C57BL/6 mice 21 days after treatment as
indicated in FIG. 8 with the respective combination therapy. The
diffuse distribution of CD8+ TIL staining (dark punctuate staining
in "D+P+B(0.6 .mu.g)") appears to be associated with higher
efficacy as compared to those with peripheral distribution of TILs
(see "D+P+B(4.0 .mu.g)" and "D+P+B(100 .mu.g)").
FIG. 14 depicts an exemplary synthetic scheme for preparation of
specifically deuterated ETRB antagonists.
FIG. 15 depicts an exemplary synthetic scheme for preparation of
intermediates for synthesis of specifically deuterated ETRB
antagonists.
FIG. 16 depicts an exemplary synthetic scheme for preparation of
intermediates for synthesis of the specifically deuterated ETRB
antagonists BQ-788-A and BQ-788-C.
FIG. 17 depicts an exemplary synthetic scheme for preparation of
the specifically deuterated ETRB antagonist BQ-788-A.
FIG. 18 depicts an exemplary synthetic scheme for preparation of
the specifically deuterated ETRB antagonist BQ-788-C.
DETAILED DESCRIPTION
Disclosed herein are specifically deuterated ETBR antagonist
compounds, compositions, and methods useful for the treatment of
cancer for example an ETBR-related cancer, e.g., malignant
melanoma, metastatic melanoma, squamous cell carcinoma,
glioblastoma, ovarian cancer, pancreatic cancer, or any combination
thereof. As described herein, specifically deuterated ETBR
antagonists as formulated herein are surprisingly advantageous for
treating ETBR-related cancers. The use of a specifically deuterated
ETBR antagonist significantly improves biologic activity relative
to the non-deuterated parent compound, as determined by measuring
serum ET-1 levels, and results in at least one of increased
stability, prolonged serum bioavailability, prolonged ETBR target
engagement, or any combination thereof. In some embodiments, the
subject treated is resistant to an immunotherapy. In some
embodiments, the composition and method disclosed herein restores
Tumor Infiltrating Lymphocytes (TILs) and/or intratumoral tertiary
lymphoid organ (TLO) formation in a tumor microenvironment.
Also disclosed herein is a combination that comprises at least one
specifically deuterated ETBR antagonist as disclosed herein, and at
least one additional anti-oncologic therapeutic agent, administered
either at the same time or at different times. In some embodiments,
the at least one anti-oncologic agent comprises a bRAF inhibitor,
an immune checkpoint inhibitor, a caspase-8 inhibitor, an ETAR
antagonist, niacinamide, a chemotherapeutic agent such as, e.g., a
taxane, a kinase inhibitor, or other receptor antagonist or
combination thereof. In some embodiments, the at least one
anti-oncologic agent is an immune checkpoint inhibitor. In some
embodiments, the immune checkpoint inhibitor is an anti-PD1
antibody or an anti-PD-L1 antibody. In some embodiments, the
anti-PD1 antibody is nivolumab, pembrolizumab, pidilizumab,
cemiplimab, or any combination thereof. In some embodiments, the
anti-PD-L1 antibody is atezolizumab, MDX-1105, avelumab,
durvalumab, or any combination thereof. In some embodiments,
specifically deuterated ETRB antagonists as described herein and
anti-oncologic agents (i.e. immunocheckpoint inhibitors such as
anti-anti-CTLA, anti-PDL1, and anti-PD1 antibodies) can be
administered at the same time (e.g. simultaneously. In some
embodiments, specifically deuterated ETRB antagonists as described
herein and anti-oncologic agents (i.e. immunocheckpoint inhibitors
such as anti-CTLA, anti-PDL1, and anti-PD1 antibodies) can be
administered at the different times (e.g. simultaneously. In some
embodiments, the specifically deuterated ETBR antagonist can be
administered once weekly, biweekly, monthly, or bimonthly. In some
embodiments, the anti-oncologic agent (i.e. immunocheckpoint
inhibitors such as anti-CTLA, anti-PDL1, and anti-PD1 antibodies)
can be administered once weekly, biweekly, monthly, or bimonthly.
In some embodiments, the specifically deuterated ETBR antagonist is
administered 2, 3, 4, or 5 times frequently as the additional
anti-oncologic agent, for example that the deuterated ETBR
antagonist is administered 3 times during 2-3 weeks (e.g., 21 days)
while the additional anti-oncologic agent is administered 1 time
during the 2-3 weeks (e.g., the 21 days). In some embodiments, the
combination comprises an effective amount of the at least one
deuterated ETBR antagonist and an effective amount of the at least
one anti-oncologic agent. In some embodiments, the combination
includes a pharmaceutically acceptable carrier for example DMSO. In
some embodiments, the combination is in separate unit dosage forms,
for example, a first container that comprises the at least one
specifically deuterated ETBR antagonist, and a second container
that comprises the at least one anti-oncologic agent. In some
embodiments, the active agents disclosed herein are in a
controlled-release delivery system comprises at least one of: (1) a
biocompatible polymer, (2) a liposome preparation; (3) a DMSO
solution, or a combination thereof.
Definitions
Unless otherwise defined, all technical and scientific terms used
herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention belongs. The
terminology used in the description is for describing particular
embodiments only and is not intended to be limiting of the
invention.
Where a range of values is provided, it is understood that each
intervening value, to the tenth of the unit of the lower limit
unless the context clearly dictates otherwise (such as in the case
of a group containing a number of carbon atoms in which case each
carbon atom number falling within the range is provided), between
the upper and lower limit of that range and any other stated or
intervening value in that stated range is encompassed within the
invention. The upper and lower limits of these smaller ranges may
independently be included in the smaller ranges is also encompassed
within the invention, subject to any specifically excluded limit in
the stated range. Where the stated range includes one or both of
the limits, ranges excluding either both of those included limits
are also included in the present disclosure.
The articles "a" and "an" as used herein and in the appended claims
are used herein to refer to one or to more than one (i.e., to at
least one) of the grammatical object of the article unless the
context clearly indicates otherwise. By way of example, "an
element" means one element or more than one element.
The phrase "and/or," as used herein in the specification and in the
claims, should be understood to mean "either or both" of the
elements so conjoined, i.e., elements that are conjunctively
present in some cases and disjunctively present in other cases.
Multiple elements listed with "and/or" should be construed in the
same fashion, i.e., "one or more" of the elements so conjoined.
Other elements may optionally be present other than the elements
specifically identified by the "and/or" clause, whether related or
unrelated to those elements specifically identified. Thus, as a
non-limiting example, a reference to "A and/or B", when used in
conjunction with open-ended language such as "comprising" can
refer, in one embodiment, to A only (optionally including elements
other than B); in another embodiment, to B only (optionally
including elements other than A); in yet another embodiment, to
both A and B (optionally including other elements); etc.
As used herein in the specification and in the claims, "or" should
be understood to have the same meaning as "and/or" as defined
above. For example, when separating items in a list, "or" or
"and/or" shall be interpreted as being inclusive, i.e., the
inclusion of at least one, but also including more than one, of a
number or list of elements, and, optionally, additional unlisted
items. Only terms clearly indicated to the contrary, such as "only
one of" or "exactly one of," or, when used in the claims,
"consisting of," will refer to the inclusion of exactly one element
of a number or list of elements. In general, the term "or" as used
herein shall only be interpreted as indicating exclusive
alternatives (i.e., "one or the other but not both") when preceded
by terms of exclusivity, such as "either," "one of," "only one of,"
or "exactly one of."
In the claims, as well as in the specification above, all
transitional phrases such as "comprising," "including," "carrying,"
"having," "containing," "involving," "holding," "composed of," and
the like are to be understood to be open-ended, i.e., to mean
including but not limited to. Only the transitional phrases
"consisting of" and "consisting essentially of" shall be closed or
semi-closed transitional phrases, respectively, as set forth in the
United States Patent Office Manual of Patent Examining Procedures,
Section 2111.03.
As used herein in the specification and in the claims, the phrase
"at least one," in reference to a list of one or more elements,
should be understood to mean at least one element selected from
anyone or more of the elements in the list of elements, but not
necessarily including at least one of each and every element
specifically listed within the list of elements and not excluding
any combinations of elements in the list of elements. This
definition also allows that elements may optionally be present
other than the elements specifically identified within the list of
elements to which the phrase "at least one" refers, whether related
or unrelated to those elements specifically identified. Thus, as a
nonlimiting example, "at least one of A and B" (or, equivalently,
"at least one of A or B," or, equivalently "at least one of A
and/or B") can refer, in one embodiment, to at least one,
optionally including more than one, A, with no B present (and
optionally including elements other than B); in another embodiment,
to at least one, optionally including more than one, B, with no A
present (and optionally including elements other than A); in yet
another embodiment, to at least one, optionally including more than
one, A, and at least one, optionally including more than one, B
(and optionally including other elements); etc.
It should also be understood that, in certain methods described
herein that include more than one step or act, the order of the
steps or acts of the method is not necessarily limited to the order
in which the steps or acts of the method are recited unless the
context indicates otherwise.
The term "combination therapy" refers to both concurrent
administration (administration of two or more therapeutic agents at
the same time) and time varied administration (administration of
one or more therapeutic agents at a time different from that of the
administration of an additional therapeutic agent or agents). In
some embodiments, the therapeutic agents are present in the patient
to some extent, for example at effective amounts, at the same time.
In some embodiments, one or more of the compounds described herein,
are administered in combination with at least one additional
bioactive agent, especially including an anticancer agent. In some
embodiments, the combination therapy of compounds results in
synergistic activity, including anticancer activity.
The term "compound", as used herein, unless otherwise indicated,
refers to any specific chemical compound disclosed herein and
includes tautomers, regioisomers, geometric isomers, and where
applicable, stereoisomers, including optical isomers (enantiomers)
and other stereoisomers (diastereomers) thereof, as well as
pharmaceutically acceptable salts and derivatives (including
prodrug forms) thereof where applicable, in context. Within its use
in context, the term compound generally refers to a single
compound, but also may include other compounds such as
stereoisomers, regioisomers and/or optical isomers (including
racemic mixtures) as well as specific enantiomers or
enantiomerically enriched mixtures of disclosed compounds. The term
also refers, in context to prodrug forms of compounds which have
been modified to facilitate the administration and delivery of
compounds to a site of activity. It is noted that in describing the
present compounds, numerous substituents and variables associated
with same, among others, are described. It is understood by those
of ordinary skill that molecules which are described herein are
stable compounds as generally described hereunder. When the bond is
shown, both a double bond and single bond are represented within
the context of the compound shown.
The terms "treat", "treating", and "treatment", etc., as used
herein, refer to any action providing a benefit to a patient for
which the present compounds may be administered, including the
treatment of any disease state or condition which is modulated
through the protein to which the present compounds bind. Disease
states or conditions, including cancer, which may be treated using
compounds according to the present disclosure, are set forth
hereinabove.
The term "anti-oncologic agent" is used to describe an anti-cancer
agent, which may be combined with compounds according to the
present disclosure to treat cancer. These agents include, for
example, everolimus, niacinamide, trabectedin, abraxane, TLK 286,
AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244
(ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin,
vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263,
a FLT-3 inhibitor, a VEGFR inhibitor, an EGFR TK inhibitor, an
aurora kinase inhibitor, a PIK-1 modulator, a Bcl-2 inhibitor, an
HDAC inhbitor, a c-MET inhibitor, a PARP inhibitor, a Cdk
inhibitor, an EGFR TK inhibitor, an IGFR-TK inhibitor, an anti-HGF
antibody, a PI3 kinase inhibitor, an AKT inhibitor, an mTORC1/2
inhibitor, a JAK/STAT inhibitor, a checkpoint-1 or 2 inhibitor, a
focal adhesion kinase inhibitor, a Map kinase kinase (mek)
inhibitor, a VEGF trap antibody, pemetrexed, erlotinib, dasatanib,
nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu,
nolatrexed, azd2171, batabulin, ofatumumab, zanolimumab,
edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen,
ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT-110,
BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001,
IPdR1 KRX-0402, lucanthone, LY317615, neuradiab, vitespan, Rta 744,
Sdx 102, talampanel, atrasentan, Xr 311, romidepsin, ADS-100380,
sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine,
doxorubicin, liposomal doxorubicin, 5'-deoxy-5-fluorouridine,
vincristine, temozolomide, ZK-304709, seliciclib; PD0325901,
AZD-6244, capecitabine, L-Glutamic acid,
N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]-
benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled
irinotecan, tamoxifen, toremifene citrate, anastrazole, exemestane,
letrozole, DES(diethyl stilbestrol), estradiol, estrogen,
conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258);
3-[5-(methylsulfonylpiperadinemethyl)-indolyl-quinolone, vatalanib,
AG-013736, AVE-0005, goserelin acetate, leuprolide acetate,
triptorelin pamoate, medroxyprogesterone acetate,
hydroxyprogesterone caproate, megestrol acetate, raloxifene,
bicalutamide, flutamide, nilutamide, megestrol acetate, CP-724714;
TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF
antibody, erbitux, EKB-569, PKI-166, GW-572016, lonafarnib,
BMS-214662, tipifarnib; amifostine, NVP-LAQ824, suberoyl analide
hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248,
sorafenib, KRN951, aminoglutethimide, arnsacrine, anagrelide,
L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, adriamycin,
bleomycin, buserelin, busulfan, carboplatin, carmustine,
chlorambucil, cisplatin, cladribine, clodronate, cyproterone,
cytarabine, dacarbazine, dactinomycin, daunorubicin,
diethylstilbestrol, epirubicin, fludarabine, fludrocortisone,
fluoxymesterone, flutamide, gleevec, gemcitabine, hydroxyurea,
idarubicin, ifosfamide, imatinib, leuprolide, levamisole,
lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna,
methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide,
octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin,
porfimer, procarbazine, raltitrexed, rituximab, streptozocin,
teniposide, testosterone, thalidomide, thioguanine, thiotepa,
tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard,
uracil mustard, estramustine, altretamine, floxuridine,
5-deooxyuridine, cytosine arabinoside, 6-mecaptopurine,
deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine,
vinorelbine, topotecan, razoxin, marimastat, COL-3, neovastat,
BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974,
interleukin-12, IM862, angiostatin, vitaxin, droloxifene,
idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab,
denileukin diftitox,gefitinib, bortezimib, paclitaxel,
cremophor-free paclitaxel, docetaxel, epithilone B, BMS-247550,
BMS-310705, droloxifene, 4-hydroxytamoxifen, pipendoxifene,
ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene,
idoxifene, TSE-424, HMR-3339, ZK186619, topotecan, PTK787/ZK
222584, VX-745, PD 184352, rapamycin,
40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001,
ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646,
wortmannin, ZM336372, L-779,450, PEG-filgrastim, darbepoetin,
erythropoietin, granulocyte colony-stimulating factor,
zolendronate, prednisone, cetuximab, granulocyte macrophage
colony-stimulating factor, histrelin, pegylated interferon alfa-2a,
interferon alfa-2a, pegylated interferon alfa-2b, interferon
alfa-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab,
hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab,
all-transretinoic acid, ketoconazole, interleukin-2, megestrol,
immune globulin, nitrogen mustard, methylprednisolone, ibritgumomab
tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene,
tositumomab, arsenic trioxide, cortisone, editronate, mitotane,
cyclosporine, liposomal daunorubicin, Edwina-asparaginase,
strontium 89, casopitant, netupitant, an NK-1 receptor antagonist,
palonosetron, aprepitant, diphenhydramine, hydroxyzine,
metoclopramide, lorazepam, alprazolam, haloperidol, droperidol,
dronabinol, dexamethasone, methylprednisolone, prochlorperazine,
granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim,
erythropoietin, epoetin alfa, darbepoetin alfa and mixtures
thereof.
The term "pharmaceutically acceptable salt" is used throughout the
specification to describe, where applicable, a salt form of one or
more of the compounds described herein which are presented to
increase the solubility of the compound in the gastric juices of
the patient's gastrointestinal tract in order to promote
dissolution and the bioavailability of the compounds.
Pharmaceutically acceptable salts include those derived from
pharmaceutically acceptable inorganic or organic bases and acids,
where applicable. Suitable salts include those derived from alkali
metals such as potassium and sodium, alkaline earth metals such as
calcium, magnesium and ammonium salts. In some embodiments, sodium
and potassium salts are suitable neutralization salts of the
phosphates.
The term "pharmaceutically acceptable derivative" is used
throughout the specification to describe any pharmaceutically
acceptable prodrug form (such as an ester, amide other prodrug
group), which, upon administration to a patient, provides directly
or indirectly the present compound or an active metabolite of the
present compound.
The term "effective" is used to describe an amount of a compound,
composition or component which, when used within the context of its
intended use, effects an intended result. The term "effective"
subsumes all other effective amount or effective concentration
terms, which are otherwise described or used in the present
application.
The term "therapeutically effective amount" refers to that amount
which is sufficient to effect treatment, as defined herein, when
administered to a mammal in need of such treatment.
The term "patient" or "subject" is used throughout the
specification to describe an animal, for example a human, or a
domesticated animal, to whom treatment, including prophylactic
treatment, with the compositions according to the present
disclosure is provided. For treatment of those infections,
conditions or disease states which are specific for a specific
animal such as a human patient, the term patient refers to that
specific animal, including a domesticated animal such as a dog or
cat or a farm animal such as a horse, cow, sheep, etc. In general,
in the present disclosure, the term patient refers to a human
patient unless otherwise stated or implied from the context of the
use of the term. Activation of the ETBR by endothelins such as ET-1
and ET-3, results in a variety of molecular events that promote
melanoma invasion and metastasis. Without being bound by any
particular theory, it is hypothesized that while the majority of
melanomas express ETBR, a subset of these also expresses the ETBR
activator ET-1 and/or ET-3. It is this subset that is therefore
most likely dependent upon ETBR activation for viability, invasive
potential and metastatic potential. Thus, this subset of patients
is most likely to respond to ETBR blockade. Furthermore, this
subset of patients is least likely to response to immune based
therapy.
The Endothelin B receptor (ETBR) pathway (FIG. 1) plays a
significant role in the metastatic spread of melanoma, and
therefore, is a target for therapeutic intervention. The Endothelin
B receptor is a 7 transmembrane G-protein coupled receptor (GPCR).
It is expressed at very low levels in normal melanocytes, but is
upregulated during melanoma development and progression. RAF and
MEK kinases, current melanoma drug targets, are activated by the
deuterated ETBR. The specific deuterated are beneficial because, as
compared to nondeuterated, there is an improvement in one or more
pharmaceutical properties (e.g. efficacy, solubility)
Endothelin-1 (ET-1) (and Endothelin-3, not shown) is a ligand that
activates the ETBR (FIG. 2). ET-1 activation of ETBR causes
melanoma cells to proliferate, metastasize and generate their own
blood supply. Our studies show that the majority of pigmented
invasive melanomas and metastatic melanomas produce ET-1 (FIG.
3).
Deuterated Compounds (Specific)
Disclosed herein is a specifically deuterated ETBR antagonist,
e.g., a deuterated form of BQ-788 as described herein. In some
embodiments, the description provides a composition comprising at
least one specifically deuterated ETBR antagonist, e.g., a
deuterated form of BQ-788 as described herein, and a
pharmaceutically acceptable carrier. In some embodiments, the
description provides a composition, e.g., a pharmaceutical
composition, comprising an effective amount of at least one
specifically deuterated ETBR antagonist, e.g., a deuterated form of
BQ-788 as described herein, and a pharmaceutically acceptable
carrier. In some embodiments, the pharmaceutical composition as
described herein can be in unit dosage form configured for
administration one or more times, for example, one or more times
per day, per week, or per month.
In some embodiments, the specifically deuterated ETBR antagonist is
a compound of the Formula (1) below:
##STR00013## wherein n is an integer from 0-5; m is an integer from
0-3; X is a positively charged counterion; R.sub.1 and R.sub.3 are
independently --H, -D, --CH.sub.3, --CH.sub.2D, --CHD.sub.2, or
--CD.sub.3; R.sub.2a, R.sub.2b, R.sub.4, R.sub.5, and R.sub.6 are
independently --CH.sub.3, --CH.sub.2D, --CHD.sub.2, or --CD.sub.3;
and at least one of R.sub.1, R.sub.2, or R.sub.3 comprises
deuterium.
In some embodiments, the specifically deuterated ETBR antagonist of
formula (1) comprises 1-8 deuterium atoms. In specific embodiments,
the specifically deuterated ETBR antagonist of formula (1)
comprises 1, 2, or 3 deuterium atoms.
In some embodiments, the specifically deuterated ETBR antagonist is
a compound of the Formula (2) below:
##STR00014##
In some embodiments, the specifically deuterated ETBR antagonist is
a compound of the Formula (3) below:
##STR00015##
In some embodiments, the specifically deuterated ETBR antagonist is
a compound of the Formula (4) below:
##STR00016##
In some embodiments, the specifically deuterated ETBR antagonist is
a compound of the Formula (5) below:
##STR00017##
In some embodiments, the specifically deuterated ETBR antagonist is
a compound of the formula (6) below:
##STR00018##
In some embodiments, the specifically deuterated ETBR antagonist of
formula (6), n is 0 or 1.
In some embodiments of the specifically deuterated ETBR antagonist
of formula (6), n is 1 and R.sup.1 is -D.
In some embodiments of the specifically deuterated ETBR antagonist
of formula (6), n is 1, R.sub.1 is -D; and R.sub.2a and R.sub.2b
are --CH.sub.3.
In some embodiments of the specifically deuterated ETBR antagonist
of formula (6), n is 0, R.sub.1 is --H; R.sub.2a is --CH.sub.3 and
R.sub.2b is --CH.sub.2D.
In some embodiments of the specifically deuterated ETBR antagonist
of formula (6), n is 0, R.sub.1 is --H; R.sub.2a is --CH.sub.2D and
R.sub.2b is --CH.sub.3.
In some embodiments of the specifically deuterated ETBR antagonist
of formula (6), n is 0, R.sub.1 is --H; and R.sub.2a and R.sub.2b
are --CH.sub.2D.
In some embodiments of the specifically deuterated ETBR antagonist
of formula (6), n is 1, R.sub.1 is -D; and R.sub.2a and R.sub.2b
are --CH.sub.2D.
In some embodiments, the specifically deuterated ETBR antagonist is
at least one of BQ-788-A, BQ-788-B, BQ-788-C, or a combination
thereof, including analogs, derivatives, polymorphs, prodrugs, and
salts thereof, including fluorinated analogues. For example, the
specifically deuterated ETBR antagonist can be a fluorinated analog
of BQ-788-A, BQ-788-B, or BQ-788-C.
In some embodiments, BQ-788-A is a specifically deuterated ETBR
antagonist depicted below:
##STR00019## a stereoisomer thereof, or a pharmaceutically
acceptable salt thereof.
In some embodiments, BQ-788-B is a specifically deuterated ETBR
antagonist depicted below:
##STR00020## a stereoisomer thereof, or a pharmaceutically
acceptable salt thereof.
In some embodiments, BQ-788-C is a specifically deuterated ETBR
antagonist depicted below:
##STR00021## a stereoisomer thereof, or a pharmaceutically
acceptable salt thereof.
In some embodiments, a compound disclosed here is of Formula
(7):
##STR00022##
a stereoisomer thereof, or a pharmaceutically acceptable salt
thereof,
wherein: each of R.sup.1, R.sup.2, R.sup.3, R.sup.4, or R.sup.5 is
independently hydrogen, halogen, hydroxyl, deuterium, halogen,
hydroxy, amino, nitro, optionally substituted C.sub.1-C.sub.8
alkyl, optionally substituted C.sub.2-C.sub.8 alkenyl, optionally
substituted C.sub.2-C.sub.8 alkynyl, optionally substituted
C.sub.3-C.sub.8 cycloalkyl, optionally substituted C.sub.1-C.sub.8
alkoxy, optionally substituted C.sub.1-C.sub.8 haloalkyl,
optionally substituted aryl, or optionally substituted heteroaryl,
optionally wherein one or more of the carbons in the piperidinyl
ring can be a heteroatom selected from O, N, or S, or wherein the
piperidinyl ring may contain one or more double bonds; R.sup.6 is
optionally substituted C.sub.1-C.sub.8 alkyl, optionally
substituted C.sub.2-C.sub.8 alkenyl, optionally substituted
C.sub.2-C.sub.8 alkynyl, optionally substituted
C.sub.3-C.sub.8-cycloalkyl, optionally substituted C.sub.1-C.sub.8
alkoxy, optionally substituted C.sub.1-C.sub.8 haloalkyl,
optionally substituted aryl, or optionally substituted heteroaryl,
wherein R.sup.6 optionally comprises deuterium; R.sup.7 is
optionally substituted cycloalkyl, optionally substituted
heterocycloalkyl, optionally substituted aryl, optionally
substituted heteroaryl, optionally substituted polycyclic ring
system, optionally substituted bicyclic, optionally substituted
heterobicyclic, wherein R.sup.7 optionally comprises deuterium;
R.sup.8 and R.sup.9 are independently optionally substituted
C.sub.1-C.sub.8 alkyl, optionally substituted C.sub.2-C.sub.8
alkenyl, optionally substituted C.sub.2-C.sub.8 alkynyl, optionally
substituted C.sub.3-C.sub.8 cycloalkyl, optionally substituted
C.sub.1-C.sub.8 alkoxy, optionally substituted C.sub.1-C.sub.8
haloalkyl, optionally substituted aryl, optionally substituted
heteroaryl, or --COOR', or R.sup.8 and R.sup.9 may be taken
together to form a optionally substituted cycloalkyl, optionally
substituted cycloalkyl heterocycloalkyl, optionally substituted
aryl, optionally substituted heteroaryl, or optionally substituted
polycyclic ring system, wherein R.sup.8 or R.sup.9 each optionally
comprises deuterium; R' is hydrogen, hydroxy, or C.sub.1-C.sub.8
alkyl; and
wherein at least one of R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7, R.sup.8, or R.sup.9 is deuterium.
In some embodiments, a compound disclosed here is of Formula
(8):
##STR00023##
a stereoisomer thereof, or a pharmaceutically acceptable salt
thereof,
wherein: each of R.sup.2, R.sup.3, or R.sup.4 is independently
hydrogen, deuterium, halogen, hydroxy, amino, nitro,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.8 alkoxy,
C.sub.1-C.sub.8 haloalkyl, aryl, or heteroaryl; R.sup.6 is
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.8 alkoxy,
C.sub.1-C.sub.8 haloalkyl, aryl, or heteroaryl, wherein R.sup.6
optionally comprises deuterium; R.sup.7 is substituted or
unsubstituted cycloalkyl, substituted or unsubstituted
heterocycloalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, or a substituted or unsubstituted
polycyclic ring system, wherein R.sup.7 optionally comprises
deuterium; R.sup.8 and R.sup.9 are independently C.sub.1-C.sub.8
alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl,
C.sub.3-C.sub.8-cycloalkyl, C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8
haloalkyl, aryl, heteroaryl, or --COOR', or R.sup.8 and R.sup.9 may
be taken together to form a substituted or unsubstituted
cycloalkyl, substituted or unsubstituted cycloalkyl
heterocycloalkyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, or substituted or unsubstituted
polycyclic ring system, wherein R.sup.8 or R.sup.9 each optionally
comprises deuterium; R' is hydrogen, hydroxy, or C.sub.1-C.sub.8
alkyl; and
wherein at least one of R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7, R.sup.8, or R.sup.9 is deuterium.
In some embodiments, a compound disclosed here is Formula (9):
##STR00024##
a stereoisomer thereof, or a pharmaceutically acceptable salt
thereof,
wherein: each of R.sup.1 R.sup.2, R.sup.3, R.sup.4, or R.sup.5 is
independently hydrogen, deuterium, halogen, hydroxy, amino, nitro,
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.8 alkoxy,
C.sub.1-C.sub.8 haloalkyl, aryl, or heteroaryl; R.sup.6 is
C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8
alkynyl, C.sub.3-C.sub.8-cycloalkyl, C.sub.1-C.sub.8 alkoxy,
C.sub.1-C.sub.8 haloalkyl, aryl, or heteroaryl, wherein R.sup.6
optionally comprises deuterium; R.sup.8 and R.sup.9 are
independently C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8 alkenyl,
C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.8 cycloalkyl, R.sup.8 and
R.sup.9 are independently C.sub.1-C.sub.8 alkyl, C.sub.2-C.sub.8
alkenyl, C.sub.2-C.sub.8 alkynyl, C.sub.3-C.sub.8-cycloalkyl,
C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8 haloalkyl, aryl,
heteroaryl, or --COOR', or R.sup.8 and R.sup.9 may be taken
together to form a substituted or unsubstituted cycloalkyl,
substituted or unsubstituted cycloalkyl heterocycloalkyl,
substituted or unsubstituted aryl, substituted or unsubstituted
heteroaryl, or substituted or unsubstituted polycyclic ring system,
wherein R.sup.8 or R.sup.9 each optionally comprises deuterium;
R.sup.10 and R.sup.10' are independently hydrogen, deuterium,
halogen, hydroxy, amino, nitro, C.sub.1-C.sub.8 alkyl,
C.sub.2-C.sub.8 alkenyl, C.sub.2-C.sub.8 alkynyl,
C.sub.3-C.sub.8-cycloalkyl, C.sub.1-C.sub.8 alkoxy, C.sub.1-C.sub.8
haloalkyl, aryl, or heteroaryl; n is an integer from 0-4; and
wherein at least one of R.sup.1, R.sup.2, R.sup.3, R.sup.4,
R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10 or R.sup.10'
is deuterium.
Pharmaceutical Compositions
Provided herein are pharmaceutical compositions comprising at least
one specifically deuterated ETBR antagonist, e.g., a deuterated
form of BQ-788 as described herein, and a pharmaceutically
acceptable carrier.
In some embodiments, the compositions herein are formulated in a
unit dosage form, including any desired carrier or excipient, and
configured for administration via any desired route, e.g., oral,
intravenous, subcutaneous, intramuscular, intraperitoneal,
parenteral, intranasal, intracranial.
In some embodiments, the compositions as described herein are
useful for the treatment of ETBR-related cancer in a patient. In
some embodiments, the cancer is a solid tumor. In some embodiments,
the cancer is at least one of breast cancer, melanoma, SCC,
glioblastoma, ovarian cancer, pancreatic cancer, or a combination
thereof.
In some embodiments, the compositions comprise a dosage of the
specifically deuterated ETBR antagonist of about 0.1 mg to about
500 mg (e.g., about 10 mg to about 100 mg), and/or a concentration
of the specifically deuterated ETBR antagonist of about 0.01 g/mL
to about 1000 mg/mL (e.g., about 0.1 mg/mL to about 5 mg/mL).
In some embodiments, the compositions as described herein are
formulated in a conventional manner using one or more
pharmaceutically acceptable carriers and may also be administered
in controlled-release formulations. Pharmaceutically acceptable
carriers that may be used in these pharmaceutical compositions
include, but are not limited to, dimethyl sulfoxide (DMSO), soybean
oil as a carrier, ion exchangers, alumina, aluminum stearate,
lecithin, serum proteins, such as human serum albumin, buffer
substances such as phosphates, glycine, sorbic acid, potassium
sorbate, partial glyceride mixtures of saturated vegetable fatty
acids, water, salts or electrolytes, such as prolamine sulfate,
disodium hydrogen phosphate, potassium hydrogen phosphate, sodium
chloride, zinc salts, colloidal silica, magnesium trisilicate,
polyvinyl pyrrolidone, cellulose-based substances, polyethylene
glycol, sodium carboxymethylcellulose, polyacrylates, waxes,
polyethylene-polyoxypropylene-block polymers, polyethylene glycol
and wool fat.
In some embodiments, the compositions include at least one of
soybean oil, dimethyl sulfoxide (DMSO), hydrogel, or a combination
thereof. Any of the embodiments described herein can be a
single-component oil phase formulation, as described above, wherein
each active ingredient can be at any of the dosages or
concentrations described herein. The single-component oil phase can
be a fixed oil, such as soybean oil. For example, the formulation
comprises about 0.1 mg to about 5.0 mg of each active ingredient in
1 mL of the single-component oil (i.e., about 0.5 mg/mL, about 1
mg/mL, or about 1.5 mg/mL of each active ingredient in the
single-component oil). The single-component oil phase formulation
can be prepared by adding each active ingredient (e.g., about 1 mg
to about 50 mg of each of the active ingredient(s)) to about 10 mL
of the single-component oil solution.
In some embodiments, pharmaceutical compositions herein comprise a
DMSO, e.g., in a DMSO solution that is about 5% to about 100% DMSO
(e.g., about 10% to about 100%, about 20% to about 100%, about 30%
to about 100%, about 40% to about 100%, about 50% to about 100%,
about 60% to about 100%, about 70% to about 100%, about 80% to
about 100%, about 90% to about 100%, about 30% to about 95%, about
45% to about 95%, about 75% to about 95%, about 30% to about 90%,
about 45% to about 90%, about 75% to about 90%, about 30% to about
85%, about 45% to about 85%, or about 75% to about 85%). For
example, the pharmaceutical compositions comprises about 0.1 mg to
about 5.0 mg of each active ingredient in 1 mL of DMSO (i.e., about
0.5 mg/mL, about 1 mg/mL, or about 1.5 mg/mL of each active
ingredient in DMSO). The DMSO pharmaceutical compositions can be
prepared by adding each active ingredient (e.g., about 1 mg to
about 50 mg of each of the active ingredient(s)) to about 10 mL of
the DMSO solution. For example, the DMSO is a DMSO solution
comprising about 5% to about 100% DMSO, about 25% to about 100%
DMSO, about 50% to about 100% DMSO, about 75% to about 100% DMSO,
about 5% to about 75% DMSO, about 25% to about 75% DMSO, about 50%
to about 75% DMSO, about 5% to about 50% DMSO, about 25% to about
50% DMSO, or about 5% to about 25% DMSO.
In some embodiments, the description provides a controlled release
subcutaneous or intramuscular dosage formulation comprising a
uniform dispersion of a specifically deuterated ETBR antagonist
(e.g., BQ-788, BQ-017, A192621, a deuterated or fluorinated analog
thereof, or combinations thereof) and an ETAR antagonist (e.g.,
BQ123) in a biocompatible delivery system whereby following
administration the deuterated ETBR and ETAR antagonists are
released slowly and simultaneously from the formulation into the
systemic circulation.
In some embodiments, the pharmaceutical composition as described
herein is formulated into a controlled release delivery system
comprising at least one biocompatible polymer. In some embodiments,
the active compounds are prepared with carriers that will protect
the compound against rapid elimination from the body, such as a
controlled release formulation, including implants, hydrogels,
thermo-sensitive hydrogels, and microencapsulated delivery systems.
Biodegradable, biocompatible polymers can be used, such as ethylene
vinyl acetate, acrylates, polycarboxylic acids, polyanhydrides,
polyglycolic acid, collagen, polyorthoesters, and polylactic acid.
In some embodiments, the biocompatible polymer is at least one of a
poly(lactide), poly(glycolide), poly(lactide-co-glycolide),
poly(lactic acid), poly(glycolic acid), poly(lactic
acid-co-glycolic acid), polycaprolactone, polycarbonate,
polyesteramide, polyanhydride, poly(amino acid), polyorthoester,
polycyanoacrylate, poly(p-dioxanone), poly(alkylene oxalate),
biodegradable polyurethane, blend, or a copolymer thereof.
In some embodiments, the pharmaceutically acceptable carrier
comprises or is a liposome. For example, the pharmaceutical
composition or formulation may comprise a liposome having an
interior volume comprising a specifically deuterated ETBR
antagonist. In some embodiments, the liposome is configured to
effectuate the controlled release of the specifically deuterated
ETBR antagonist, e.g., rapid release, extended release, or a
combination thereof.
In some embodiments, the liposome is configured to effectuate the
controlled release of the pharmaceutical compositions. In some
embodiments, the liposome is configured to effectuate rapid release
of the pharmaceutical compositions. In other embodiments, the
liposome is configured or formulated to effectuate extended release
the pharmaceutical compositions. In some embodiments, the liposome
is configured to result in both the rapid and extended release of
pharmaceutical compositions.
In some embodiments, the liposome is configured to effectuate the
controlled release of the specifically deuterated ETBR antagonist
or the caspase-8 inhibitor or a combination thereof. In some
embodiments, the liposome is configured to effectuate rapid release
of the specifically deuterated ETBR antagonist or the caspase-8
inhibitor or a combination thereof. In other embodiments, the
liposome is configured or formulated to effectuate extended release
the specifically deuterated ETBR antagonist or the caspase-8
inhibitor or a combination thereof. In some embodiments, the
liposome is configured to result in both the rapid and extended
release of the specifically deuterated ETBR antagonist or the
caspase-8 inhibitor or a combination thereof.
In some embodiments, liposomal suspensions are pharmaceutically
acceptable carriers. For example, liposome formulations may be
prepared by dissolving appropriate lipid(s) (such as stearoyl
phosphatidyl ethanolamine, stearoyl phosphatidyl choline,
arachadoyl phosphatidyl choline, and cholesterol) in an inorganic
solvent that is then evaporated, leaving behind a thin film of
dried lipid on the surface of the container. An aqueous solution of
the active compound is then introduced into the container. The
container is then swirled by hand to free lipid material from the
sides of the container and to disperse lipid aggregates, thereby
forming the liposomal suspension.
In some embodiments, the pharmaceutical compositions comprise a
liposome having an interior volume comprising a specifically
deuterated ETBR antagonist or a caspase-8 inhibitor or a
combination thereof, and an effective amount of at least one of an
ETAR antagonist, an anti-PD1 antibody, a bRAF inhibitor,
niacinamide or a combination thereof. In some embodiments, the
liposome comprises at least one of a neutral lipid, a basic (having
a net positive charge) lipid, an acidic (having a net negative
charge) lipid, cholesterol, or a combination thereof. In some
embodiments, the liposome further comprises a polymeric component.
In some embodiments, the interior volume of the liposome is at
least partially aqueous, and comprises a specifically deuterated
ETBR antagonist.
In some embodiments, the description provides the pharmaceutical
composition as described herein in a liposomal delivery system,
e.g., at least one of a phosphatidylethanolamine (PE) such as
dipalmitoyl PE (DPPE), and partially unsaturated
phosphatidylcholine (PC), such as egg PC (EPC) or SPC, fully
unsaturated PC such as HSPC, PG, phosphatidylserine (PS),
phosphatidylinositol (PI) or a combination thereof. In some
embodiments, the phospholipid is at least one of a partially
unsaturated PG, dipalmitoylphosphatidylglycerol (DPPG),
cholesterol, DSPE-PEG2000, polysorbate-80 or combination thereof.
In some embodiments, the liposomal delivery system is a controlled
release system, e.g., at least one of rapid release, extended
release, rapid and extended release, delayed release, sustained
release, slow release, and combinations thereof.
In some embodiments, the pharmaceutical compositions herein
comprise pharmaceutically acceptable salts, in particular, acid or
base addition salts of compounds as described herein. The acids
which are used to prepare the pharmaceutically acceptable acid
addition salts of the aforementioned base compounds useful
according to this aspect are those which form non-toxic acid
addition salts, i.e., salts containing pharmacologically acceptable
anions, such as the hydrochloride, hydrobromide, hydroiodide,
nitrate, sulfate, bisulfate, bitartrate, phosphate, acid phosphate,
acetate, lactate, citrate, acid citrate, tartrate, bitartrate,
succinate, maleate, fumarate, gluconate, saccharate, benzoate,
methanesulfonate, ethanesulfonate, benzenesulfonate,
p-toluenesulfonate and pamoate [i.e.,
1,1'-methylene-bis-(2-hydroxy-3 naphthoate)]salts, among numerous
others. Pharmaceutically acceptable base addition salts may also be
used to produce pharmaceutically acceptable salt forms of the
compounds or derivatives according to the present disclosure. The
chemical bases that may be used as reagents to prepare
pharmaceutically acceptable base salts of the present compounds
that are acidic in nature are those that form nontoxic base salts
with such compounds. Such non-toxic base salts include, but are not
limited to those derived from such pharmacologically acceptable
cations such as alkali metal cations (eg., potassium and sodium)
and alkaline earth metal cations (e.g., calcium, zinc and
magnesium), ammonium or water-soluble amine addition salts such as
N-methylglucamine-(meglumine), and the lower alkanolammonium and
other base salts of pharmaceutically acceptable organic amines,
among others.
In some embodiments, oral compositions include an inert diluent or
an edible carrier. They may be enclosed in gelatin capsules or
compressed into tablets. For the purpose of oral therapeutic
administration, the active compound or its prodrug derivative can
be incorporated with excipients and used in the form of tablets,
troches, or capsules. Pharmaceutically compatible binding agents,
and/or adjuvant materials can be included as part of the
composition. The tablets, pills, capsules, troches and the like can
contain any of the following ingredients, or compounds of a similar
nature: a binder such as microcrystalline cellulose, gum tragacanth
or gelatin; an excipient such as starch or lactose, a dispersing
agent such as alginic acid, Primogel, or corn starch; a lubricant
such as magnesium stearate or Sterotes; a glidant such as colloidal
silicon dioxide; a sweetening agent such as sucrose or saccharin;
or a flavoring agent such as peppermint, methyl salicylate, or
orange flavoring. When the dosage unit form is a capsule, it can
contain, in addition to material of the above type, a liquid
carrier such as a fatty oil. In addition, dosage unit forms can
contain various other materials which modify the physical form of
the dosage unit, for example, coatings of sugar, shellac, or
enteric agents.
In some embodiments, the active compound or pharmaceutically
acceptable salt thereof is administered as a component of an
elixir, suspension, syrup, wafer, chewing gum or the like. A syrup
may contain, in addition to the active compounds, sucrose as a
sweetening agent and certain preservatives, dyes and colorings and
flavors.
In some embodiments, solutions or suspensions used for parenteral,
intradermal, subcutaneous, intravenous, intramuscular, or topical
application include the following components: a sterile diluent
such as water for injection, saline solution, fixed oils (e.g.,
soybean oil), polyethylene glycols, glycerine, propylene glycol or
other synthetic solvents; antibacterial agents such as benzyl
alcohol or methyl parabens; antioxidants such as ascorbic acid or
sodium bisulfite; chelating agents such as
ethylenediaminetetraacetic acid; buffers such as acetates, citrates
or phosphates and agents for the adjustment of tonicity such as
sodium chloride or dextrose. The parental preparation can be
enclosed in ampoules, disposable syringes or multiple dose vials
made of glass or plastic. In some embodiments, carriers for
intravenous administration are physiological saline or phosphate
buffered saline (PBS).
Combination Therapy
Disclosed herein are pharmaceutical compositions for therapeutic
combinations, in a single dosage form or separate dosage forms
administered concurrently or separately, comprising at least one of
specifically deuterated ETBR antagonist as described herein, and at
least one additional anti-oncologic agent. In some embodiments, the
at least one additional anti-oncologic agent is an immune
checkpoint inhibitor, e.g., an anti-PD1 antibody or anti-PD-L1
antibody. In some embodiments, the specifically deuterated ETBR
antagonist is administered 2, 3, 4, or 5 times frequently as the
additional anti-oncologic agent, for example that the specifically
deuterated ETBR antagonist is administered 3 times during 1-3 weeks
(e.g., about 2-3 weeks or about 21 days) while the additional
anti-oncologic agent is administered 1 time during the 1-3 weeks
(e.g., about 2-3 weeks or about 21 days).
In some embodiments, the pharmaceutical compositions as described
herein demonstrate a synergistic effect in that the pharmaceutical
compositions achieve at least one of: a greater therapeutic effect
(i.e., more efficacious) than the additive therapeutic effect
obtained by administration of the constituent ingredients alone, a
greater therapeutic effect than achieved by administration of a
higher dose of the constituent ingredients alone, a similar or
greater therapeutic effect but with a decrease in adverse events or
side effects relative to that observed by administration of the
constituent ingredients alone (i.e., improved therapeutic window),
or increased duration of effects, or a similar or greater
therapeutic effect at a smaller dose of one or both of the
constituent ingredients or a combination thereof.
In some embodiments, the description provides pharmaceutical
compositions comprising a first composition comprising a
specifically deuterated ETBR antagonist as described herein in an
amount effective when administered with at least one additional
anticancer or anti-oncologic agent; and a second composition
comprising an effective amount of the at least one additional
anticancer or anti-oncologic agent as described herein.
In some embodiments, the description provides a combination
comprising at least one ETBR antagonist, e.g., a specifically
deuterated ETBR antagonist, and at least one additional
anti-oncologic therapeutic agent. In some embodiments, the at least
one anti-oncologic agent is a bRaf inhibitor, an immune checkpoint
inhibitor, a caspase-8 inhibitor, an ETAR antagonist, niacinamide,
a chemotherapeutic agent such as, e.g., a taxane, a kinase
inhibitor, or other receptor antagonist or combination thereof. In
some embodiments, the pharmaceutical compositions comprise an
effective amount (e.g., a synergistically effective amount) of at
least two of specifically deuterated ETBR antagonist, bRaf
inhibitor, an immune checkpoint inhibitor, a caspase-8 inhibitor,
an ETAR antagonist, niacinamide, a chemotherapeutic agent such as,
e.g., a taxane, a kinase inhibitor, or other receptor antagonist or
combination thereof.
In some embodiments, the specifically deuterated ETBR antagonist
and the at least one additional anti-oncologic therapeutic agent
are comprised in separate pharmaceutical compositions. In some
embodiments, the specifically deuterated ETBR antagonist and the at
least one additional anti-oncologic therapeutic agent are comprised
in the same pharmaceutical composition.
In some embodiments, the description provides methods comprising
administering a specifically deuterated ETBR antagonist as
described herein in an amount effective for treating cancer and an
anti-oncologic agent, and a pharmaceutically acceptable excipient
or carrier. In some embodiments, the specifically deuterated ETBR
antagonist is at least one of a deuterated BQ-788, BQ-017, A192621,
BQ-788-A, BQ-788-B, or BQ-788-C or a combination thereof.
In some embodiments, the description provides a pharmaceutical
composition comprising a specifically deuterated ETBR antagonist as
described herein in an amount effective for treating cancer, and a
pharmaceutically acceptable carrier. In some embodiments, the
amount is effective to treat cancer when also administered with at
least one additional anti-oncologic agent, and a pharmaceutically
acceptable excipient or carrier. In some embodiments, the
specifically deuterated ETBR antagonist is at least one of a
deuterated BQ-788, BQ-017, A192621, BQ-788-A, BQ-788-B, or BQ-788-C
or a combination thereof.
In some embodiments, the description provides a therapeutic
combination comprising, in the same or separate dosage forms, an
effective amount of the at least one ETBR antagonist and an
effective amount of at least one anti-oncologic agent. In some
embodiments, the combination comprises a synergistically effective
amount of the at least one ETBR antagonist. In some embodiments,
the combination comprises a synergistically effective amount of the
at least one anti-oncologic agent. In some embodiments, the
combination includes a pharmaceutical acceptable carrier. In some
embodiments, the combination or formulation is comprised in one or
more unit dosage forms. In further embodiments, the combination is
comprised in separate unit dosage forms, for example, a first
container comprising the at least one ETBR antagonist, and a second
container comprising the at least one anti-oncologic agent. In some
embodiments, the ETBR antagonist is a specifically deuterated ETBR
antagonist as described herein.
In some embodiments, the description provides a combination therapy
comprising administering: (a) a first composition comprising an
effective amount of a specifically deuterated ETBR antagonist and a
pharmaceutically acceptable carrier or excipient; and (b) a second
composition comprising an effective amount of at least one
additional anti-oncologic agent, and a pharmaceutically acceptable
carrier or excipient, wherein the administering demonstrates
synergistic anti-cancer activity. In some embodiments, the
specifically deuterated ETBR antagonist is a deuterated BQ-788 as
described herein.
In some embodiments, the at least one anti-oncologic agent is an
immune checkpoint inhibitor. In some embodiments, the immune
checkpoint inhibitor is an anti-PD1 antibody or an anti-PD-L1
antibody. In some embodiments, the anti-PD1 antibody is at least
one of nivolumab, pembrolizumab, pidilizumab, or any combination
thereof. In some embodiments, the anti-PD-L1 antibody is
atezolizumab, MDX-1105, avelumab, durvalumab, or any combination
thereof.
In some embodiments, the bRAF inhibitor is at least one of
dabrafenib, sorafenib, vemurafenib, or any other bRAF inhibitor
known or that becomes known to one skilled in the art.
In some embodiments, caspase-8 is a downstream effector of the
ETBR, and caspase-8 inhibitors block molecular events that promote
invasion and metastasis that are triggered as a result of ETBR
activation. As such, caspase-8 inhibitors can be classified as a
caspase-8 antagonist or an antagonist/inhibitor of ETBR signaling.
In some embodiments, the caspase-8 inhibitor peptide has a sequence
of Ac-AAVALLPAVLLAALAPIETD-CHO, which is commercially available
from EMD Millipore (Billerica, Mass. 01821, USA).
In some embodiments, the physiologic role of the ETBR is to clear
excess levels of endothelin-1 (ET-1), from the circulation. Without
being bound by any particular theory, it is hypothesized that
administering a specifically deuterated ETBR antagonist prevents
ET-1 clearance and elevates serum ET-1 levels. Elevated serum
levels of ET-1 are associated with a variety of adverse effects due
to its activation of the Endothelin A receptor (ETAR) including,
hypertension, pulmonary hypertension and renal vasoconstriction. In
some embodiments, in order to minimize the unwanted effect of ETAR
activation, the description provides pharmaceutical compositions
and methods for combination therapy (in a single dosage form or
separate dosage forms administered approximately contemporaneously)
of a specifically deuterated ETBR antagonist with an ETAR
antagonist. The ETAR antagonist acts synergistically to enhance the
beneficial effects of a specifically deuterated ETBR antagonist
while minimizing adverse events or side effects. It was also
surprising that an effective amount (e.g., a synergistically
effective amount) of niacinamide was effective at synergistically
minimizing adverse events or side effects, such as weight loss,
from the specifically deuterated ETBR antagonist. The formulations
as described herein are useful for the treatment of cancer in a
patient, for example, breast cancer, melanoma, SCC, glioblastoma;
solid tumors or a combination thereof.
In some embodiments, the ETAR antagonist is BQ123. BQ123
(2-[(3R,6R,9S,12R,15S)-6-(1H-indol-3-ylmethyl)-9-(2-methylpropyl)-2,5,8,1-
1,14-pentaoxo-12-propan-2-yl-1,4,7,10,13-pentazabicyclo[13.3.0]octadecan-3-
-yl]acetic acid or cyclo(D-Trp-D-Asp-Pro-D-Val-Leu)) is a selective
ETAR antagonist. (Ishikawa et al., (1992). "Cyclic pentapeptide
endothelin antagonists with high ETA selectivity. Potency- and
solubility-enhancing modifications." Journal of Medicinal Chemistry
35 (11): 1239-42, which is incorporated herein by reference). BQ123
is available commercially from, e.g., ABI Chem (AC1L9EDH).
In some embodiments, pharmaceutical compositions herein comprise an
effective amount of a specifically deuterated ETBR antagonist in
combination with an effective amount of an ETAR antagonist, and a
pharmaceutically acceptable carrier. In some embodiments, the
effective amount of an ETAR is a synergistically effective amount.
In some embodiments, the specifically deuterated ETBR antagonist is
at least one of a deuterated form of BQ-788, A192621, or a
combination thereof, including analogs, derivatives, polymorphs,
prodrugs, and salts thereof. In some embodiments, the ETAR
antagonist is BQ123, including analogs, derivatives, polymorphs,
prodrugs, and salts thereof.
In some embodiments, the additional anti-oncologic agent is at
least one of apx005m, ipilimumab, vemurafenib, dacabazine,
nivolumab, pembrolizumab, niacinamide, interleukin-2, DEDN6526,
Talimogene laherparepvec, tumor infiltrating lymphocytes, an
anti-angiogenic agent, adriamycin, camptothecin, carboplatin,
cisplatin, daunorubicin, doxorubicin, alpha, beta, or gamma
interferon, irinotecan, docetaxel, paclitaxel, topotecan,
atrasentan, tezosentan, bosentan, sitaxsentan, enrasentan,
zibotentan, Ro468443, TBC10950, TBC10894, A192621, A308165,
SB209670, SB17242, A182086, (s)-Lu302872, J-104132, TAK-044,
Sarafotoxin 56c, IRL2500, RES7011, Aselacins A, B, and C, Ro470203,
Ro462005, sulfamethoxazole, cochinmicin I, II, and III, L749329,
L571281, L754142, J104132, CGS27830, PD142893, PD143296, PD145065,
PD156252, PD159020, PD160672, PD160874, TM-ET-1, IRL3630, Ro485695,
L75037, LU224332, PD142893, LU302872, PD145065, Ro610612, SB217242,
or a combinations thereof. In some embodiments, the additional
anti-oncologic agent is a RAF kinase antagonist, a MEK antagonist
or a combination thereof. In some embodiments, the anti-oncologic
agent is at least one of an IDO inhibitor, HDAC inhibitor, DNMT
inhibitor, adenosine receptor inhibitor, CXCR4/CXCL12 axis
inhibitor or a combination thereof. In some embodiments, the DNMT
inhibitor is vidaza. In some embodiments, the HDAC inhibitor is at
least one of entinostat, mocetinostat, inostat, romidepsin,
ACY-241, farydak or a combination thereof. In some embodiments, the
adenosine receptor inhibitor is at least one of CPI-444 (V81444),
PBF-509, MEDI9447, MK-3814, AZD4635, BMS-986179 or a combination
thereof. In some embodiments, the CXCR4/CXCL12 axis inhibitor is at
least one of ulocuplumab, BL-8040, PF-06747143, POL6326,
plerixafor, ALX-0651, LY2510924, AMD11070, X4P-001, Q122, USL311,
burixafor hyrobromid, CX-01, CTCE 9908, GMI-1359 or a combination
thereof. In some embodiments, the anti-oncologic agent is an
anti-angiogenic agent selected from thalidomide, marimastat, COL-3,
BMS275291, squalamine, 2-ME, SU6668, neovastat, Medi522, EMD121974,
CAI, celecoxib, interleukin-12, IM862, TNP470, avastin, gleevac,
herceptin, or a combination thereof. In some embodiments, the
anti-oncologic agent is a cell CDK4/6 cycle inhibitor, for example,
ribociclib, palbociclib, milciclib, voruciclib, abemaciclib,
flavopiridol or a combination thereof.
In some embodiments, a dosage of the specifically deuterated ETBR
antagonist is about 0.1 .mu.g to about 500 mg (e.g., about 100
.mu.g to about 4000 .mu.g) and/or a concentration of the
specifically deuterated ETBR antagonist is about 0.01 .mu.g/mL to
about 1000 mg/mL of the composition (e.g., about 0.1 mg/mL to about
5 mg/mL).
In some embodiments, a dosage of the ETAR antagonist is about 0.1
.mu.g to about 500 mg (e.g., about 100 .mu.g to about 4000 .mu.g)
and/or a concentration of the ETAR antagonist is about 0.01 g/mL to
about 1000 mg/mL of the composition (e.g., about 0.1 mg/mL to about
5 mg/mL).
In some embodiments, a dosage of the anti-PD1 antibody is about 0.1
.mu.g to about 500 mg (e.g., about 100 .mu.g to about 4000 .mu.g)
and/or a concentration of the anti-PD1 antibody is about 0.01
.mu.g/mL to about 1000 mg/mL of the composition (e.g., about 0.1
mg/mL to about 5 mg/mL).
In some embodiments, a dosage of the bRAF inhibitor is about 0.1
.mu.g to about 500 mg (e.g., about 100 .mu.g to about 4000 .mu.g)
and/or a concentration of the bRAF inhibitor is about 0.01 g/mL to
about 1000 mg/mL of the composition (e.g., about 0.1 mg/mL to about
5 mg/mL).
In some embodiments, a dosage of the niacinamide is about 0.1 .mu.g
to about 500 mg (e.g., about 100 .mu.g to about 4000 .mu.g) and/or
a concentration of the niacinamide is about 0.01 .mu.g/mL to about
1000 mg/mL of the composition (e.g., about 0.1 mg/mL to about 5
mg/mL).
In some embodiments, a dosage of the caspase-8 inhibitor is about
0.1 .mu.g to about 500 mg (e.g., about 100 .mu.g to about 4000
.mu.g or about 1 .mu.g to about 4000 .mu.g) and/or a concentration
of the caspase-8 inhibitor is about 0.01 .mu.g/mL to about 1000
mg/mL of the composition (e.g., about 0.1 mg/mL to about 5
mg/mL).
In some embodiments, the concentration of the at least one
specifically deuterated ETBR antagonist, and/or the at least one
anti-oncologic agent can independently be about 0.01 .mu.g/mL to
about 1000 mg/mL, about 0.01 .mu.g/mL to about 750 mg/mL, about
0.01 .mu.g/mL to about 500 mg/mL, about 0.01 .mu.g/mL to about 300
mg/mL, about 0.01 .mu.g/mL to about 150 mg/mL, about 0.01 .mu.g/mL
to about 100 mg/mL, about 0.01 .mu.g/mL to about 50 mg/mL, about
0.01 .mu.g/mL to about 25 mg/mL, about 0.01 .mu.g/mL to about 10
mg/mL, about 0.01 .mu.g/mL to about 1.0 mg/mL, about 0.01 .mu.g/mL
to about 0.1 .mu.g/mL, about 0.1 .mu.g/mL to about 750 mg/mL, about
0.1 .mu.g/mL to about 500 mg/mL, about 0.1 .mu.g/mL to about 300
mg/mL, about 0.1 .mu.g/mL to about 150 mg/mL, about 0.1 .mu.g/mL to
about 100 mg/mL, about 0.1 .mu.g/mL to about 50 mg/mL, about 0.1
.mu.g/mL to about 25 mg/mL, about 0.1 .mu.g/mL to about 10 mg/mL,
about 0.1 .mu.g/mL to about 1.0 mg/mL, about 1.0 .mu.g/mL to about
750 mg/mL, about 1.0 .mu.g/mL to about 500 mg/mL, about 1.0
.mu.g/mL to about 300 mg/mL, about 1.0 g/mL to about 150 mg/mL,
about 1.0 .mu.g/mL to about 100 mg/mL, about 1.0 .mu.g/mL to about
50 mg/mL, about 1.0 .mu.g/mL to about 25 mg/mL, about 1.0 .mu.g/mL
to about 10 mg/mL, about 10 .mu.g/mL to about 750 mg/mL, about 10
.mu.g/mL to about 500 mg/mL, about 10 .mu.g/mL to about 300 mg/mL,
about 10 .mu.g/mL to about 150 mg/mL, about 10 .mu.g/mL to about
100 mg/mL, about 10 .mu.g/mL to about 50 mg/mL, about 10 .mu.g/mL
to about 25 mg/mL, about 25 .mu.g/mL to about 750 mg/mL, about g/mL
to about 500 mg/mL, about 25 .mu.g/mL to about 300 mg/mL, about 25
.mu.g/mL to about 150 mg/mL, about 25 .mu.g/mL to about 100 mg/mL,
about 25 .mu.g/mL to about 50 mg/mL, about 50 .mu.g/mL to about 750
mg/mL, about 50 .mu.g/mL to about 500 mg/mL, about 50 .mu.g/mL to
about 300 mg/mL, about 50 .mu.g/mL to about 150 mg/mL, about 50
.mu.g/mL to about 100 mg/mL, about 100 .mu.g/mL to about 750 mg/mL,
about 100 .mu.g/mL to about 500 mg/mL, about 100 .mu.g/mL to about
300 mg/mL, about 100 .mu.g/mL to about 150 mg/mL, about 150
.mu.g/mL to about 750 mg/mL, about 150 .mu.g/mL to about 500 mg/mL,
about 150 .mu.g/mL to about 300 mg/mL, about 300 .mu.g/mL to about
750 mg/mL, about 300 .mu.g/mL to about 500 mg/mL, or about 500
.mu.g/mL to about 750 mg/mL.
In some embodiments, the dosage of the at least one specifically
deuterated ETBR antagonist, and/or at least one anti-oncologic
agent can independently be about 0.1 .mu.g to about 5000 Gg, about
0.1 .mu.g to about 4500 .mu.g, about 0.1 .mu.g to about 4000 .mu.g,
about 0.1 .mu.g to about 3500 .mu.g, about 0.1 .mu.g to about 3000
.mu.g, about 0.1 .mu.g to about 2500 .mu.g, about 0.1 .mu.g to
about 2000 .mu.g, about 0.1 .mu.g to about 1500 .mu.g, about 0.1
.mu.g to about 1000 .mu.g, about 0.1 .mu.g to about 500 .mu.g,
about 1.0 .mu.g to about 5000 .mu.g, about 1.0 .mu.g to about 4500
.mu.g, about 1.0 .mu.g to about 4000 .mu.g, about 1.0 .mu.g to
about 3500 .mu.g, about 1.0 .mu.g to about 3000 .mu.g, about 1.0
.mu.g to about 2500 .mu.g, about 1.0 .mu.g to about 2000 .mu.g,
about 1.0 .mu.g to about 1500 .mu.g, about 1.0 g to about 1000
.mu.g, about 1.0 .mu.g to about 500 .mu.g, about 100 .mu.g to about
5000 .mu.g, about 100 .mu.g to about 4500 .mu.g, about 100 .mu.g to
about 4000 .mu.g, about 100 .mu.g to about 3500 .mu.g, about 100
.mu.g to about 3000 .mu.g, about 100 .mu.g to about 2500 .mu.g,
about 100 .mu.g to about 2000 .mu.g, about 100 .mu.g to about 1500
.mu.g, about 100 .mu.g to about 1000 .mu.g, about 100 .mu.g to
about 500 .mu.g, about 250 .mu.g to about 5000 .mu.g, about 250
.mu.g to about 4500 .mu.g, about 250 .mu.g to about 4000 .mu.g,
about 250 .mu.g to about 3500 .mu.g, about 250 .mu.g to about 3000
.mu.g, about 250 g to about 2500 .mu.g, about 250 .mu.g to about
2000 .mu.g, about 250 .mu.g to about 1500 .mu.g, about 250 .mu.g to
about 1000 .mu.g, about 250 .mu.g to about 500 .mu.g, about 500
.mu.g to about 5000 .mu.g, about 500 .mu.g to about 4500 .mu.g,
about 500 .mu.g to about 4000 .mu.g, about 500 .mu.g to about 3500
.mu.g, about 500 .mu.g to about 3000 .mu.g, about 500 .mu.g to
about 2500 .mu.g, about 500 .mu.g to about 2000 .mu.g, about 500
.mu.g to about 1500 .mu.g, about 500 .mu.g to about 1000 .mu.g,
about 750 .mu.g to about 5000 .mu.g, about 750 .mu.g to about 4500
.mu.g, about 750 .mu.g to about 4000 .mu.g, about 750 .mu.g to
about 3500 .mu.g, about 750 .mu.g to about 3000 .mu.g, about 750
.mu.g to about 2500 .mu.g, about 750 .mu.g to about 2000 .mu.g,
about 75 .mu.g to about 1500 .mu.g, about 750 .mu.g to about 1000
.mu.g, about 1500 .mu.g to about 5000 .mu.g, about 1500 .mu.g to
about 4500 .mu.g, about 1500 .mu.g to about 4000 .mu.g, about 1500
.mu.g to about 3500 .mu.g, about 1500 .mu.g to about 3000 .mu.g,
about 1500 .mu.g to about 2500 .mu.g, about 1500 .mu.g to about
2000 .mu.g, about 2000 .mu.g to about 5000 .mu.g, about 2000 .mu.g
to about 4500 .mu.g, about 2000 .mu.g to about 4000 .mu.g, about
2000 .mu.g to about 3500 .mu.g, about 2000 .mu.g to about 3000
.mu.g, about 2000 .mu.g to about 2500 .mu.g, about 2500 .mu.g to
about 5000 .mu.g, about 2500 .mu.g to about 4500 .mu.g, about 2500
.mu.g to about 4000 .mu.g, about 2500 .mu.g to about 3500 .mu.g,
about 2500 .mu.g to about 3000 .mu.g, about 3000 .mu.g to about
5000 .mu.g, about 3000 .mu.g to about 4500 .mu.g, about 3500 .mu.g
to about 4000 .mu.g, about 3500 .mu.g to about 5000 .mu.g, about
3500 .mu.g to about 4500 .mu.g, about 3500 .mu.g to about 4000
.mu.g, about 4000 .mu.g to about 5000 .mu.g, about 4000 .mu.g to
about 4500 .mu.g, or about 4500 .mu.g to about 5000 .mu.g.
In some embodiments, a dosage of the anti-PD1 antibody is about 0.1
mg/kg to about 9.0 mg/kg. For example, the dosage of the anti-PD1
antibody is about 0.1 mg/kg to about 9.0 mg/kg, about 0.1 mg/kg to
about 8.0 mg/kg, about 0.1 mg/kg to about 7.0 mg/kg, about 0.1
mg/kg to about 6.0 mg/kg, about 0.1 mg/kg to about 5.0 mg/kg, about
0.1 mg/kg to about 4.0 mg/kg, about 0.1 mg/kg to about 3.0 mg/kg,
about 0.1 mg/kg to about 2.0 mg/kg, about 0.1 mg/kg to about 1.0
mg/kg, about 1.0 mg/kg to about 9.0 mg/kg, about 1.0 mg/kg to about
8.0 mg/kg, about 1.0 mg/kg to about 7.0 mg/kg, about 1.0 mg/kg to
about 6.0 mg/kg, about 1.0 mg/kg to about 5.0 mg/kg, about 1.0
mg/kg to about 4.0 mg/kg, about 1.0 mg/kg to about 3.0 mg/kg, about
1.0 mg/kg to about 2.0 mg/kg, about 2.0 mg/kg to about 9.0 mg/kg,
about 2.0 mg/kg to about 8.0 mg/kg, about 2.0 mg/kg to about 7.0
mg/kg, about 2.0 mg/kg to about 6.0 mg/kg, about 2.0 mg/kg to about
5.0 mg/kg, about 2.0 mg/kg to about 4.0 mg/kg, about 2.0 mg/kg to
about 3.0 mg/kg, about 3.0 mg/kg to about 9.0 mg/kg, about 3.0
mg/kg to about 8.0 mg/kg, about 3.0 mg/kg to about 7.0 mg/kg, about
3.0 mg/kg to about 6.0 mg/kg, about 3.0 mg/kg to about 5.0 mg/kg,
about 3.0 mg/kg to about 4.0 mg/kg, about 4.0 mg/kg to about 9.0
mg/kg, about 4.0 mg/kg to about 8.0 mg/kg, about 4.0 mg/kg to about
7.0 mg/kg, about 4.0 mg/kg to about 6.0 mg/kg, about 4.0 mg/kg to
about 5.0 mg/kg, about 5.0 mg/kg to about 9.0 mg/kg, about 5.0
mg/kg to about 8.0 mg/kg, about 5.0 mg/kg to about 7.0 mg/kg, about
5.0 mg/kg to about 6.0 mg/kg, about 6.0 mg/kg to about 9.0 mg/kg,
about 6.0 mg/kg to about 8.0 mg/kg, about 6.0 mg/kg to about 7.0
mg/kg, about 7.0 mg/kg to about 9.0 mg/kg, about 7.0 mg/kg to about
8.0 mg/kg, or about 8.0 mg/kg to about 9.0 mg/kg.
In some embodiments, a dosage of the bRAF inhibitor is about 1 mg
to about 1500 mg. For example, the dosage of the bRAF inhibitor
about 1 mg to about 1500 mg, about 1 mg to about 1250 mg, about 1
mg to about 1000 mg, about 1 mg to about 750 mg, about 1 mg to
about 500 mg, about 1 mg to about 250 mg, about 250 mg to about
1500 mg, about 250 mg to about 1250 mg, about 250 mg to about 1000
mg, about 250 mg to about 750 mg, about 250 mg to about 500 mg,
about 500 mg to about 1500 mg, about 500 mg to about 1250 mg, about
500 mg to about 1000 mg, about 500 mg to about 750 mg, about 750 mg
to about 1500 mg, about 750 mg to about 1250 mg, about 750 mg to
about 1000 mg, about 1000 mg to about 1500 mg, about 1000 mg to
about 1250 mg, or about 1250 mg to about 1500 mg.
In some embodiments, a dosage of the niacinamide is about 1 mg to
about 3000 mg. For example, the dosage of the niacinamide is about
1 mg to about 3000 mg, about 1 mg to about 2750 mg, about 1 mg to
about 2500 mg, about 1 mg to about 2250 mg, about 1 mg to about
2000 mg, about 1 mg to about 1750 mg, about 1 mg to about 1500 mg,
about 1 mg to about 1250 mg, about 1 mg to about 1000 mg, about 1
mg to about 750 mg, about 1 mg to about 500 mg, about 1 mg to about
250 mg, about 250 mg to about 3000 mg, about 250 mg to about 2750
mg, about 250 mg to about 2500 mg, about 250 mg to about 2250 mg,
about 250 mg to about 2000 mg, about 250 mg to about 1750 mg, about
250 mg to about 1500 mg, about 250 mg to about 1250 mg, about 250
mg to about 1000 mg, about 250 mg to about 750 mg, about 250 mg to
about 500 mg, about 500 mg to about 3000 mg, about 500 mg to about
2750 mg, about 500 mg to about 2500 mg, about 500 mg to about 2250
mg, about 500 mg to about 2000 mg, about 500 mg to about 1750 mg,
about 500 mg to about 1500 mg, about 500 mg to about 1250 mg, about
500 mg to about 1000 mg, about 500 mg to about 750 mg, about 750 mg
to about 3000 mg, about 750 mg to about 2750 mg, about 750 mg to
about 2500 mg, about 750 mg to about 2250 mg, about 750 mg to about
2000 mg, about 750 mg to about 1750 mg, about 750 mg to about 1500
mg, about 750 mg to about 1250 mg, about 750 mg to about 1000 mg,
about 1000 mg to about 3000 mg, about 1000 mg to about 2750 mg,
about 1000 mg to about 2500 mg, about 1000 mg to about 2250 mg,
about 1000 mg to about 2000 mg, about 1000 mg to about 1750 mg,
about 1000 mg to about 1500 mg, about 100 mg to about 1250 mg,
about 1250 mg to about 3000 mg, about 1250 mg to about 2750 mg,
about 1250 mg to about 2500 mg, about 1250 mg to about 2250 mg,
about 1250 mg to about 2000 mg, about 1250 mg to about 1750 mg,
about 1250 mg to about 1500 mg, about 1500 mg to about 3000 mg,
about 1500 mg to about 2750 mg, about 1500 mg to about 2500 mg,
about 1500 mg to about 2250 mg, about 1500 mg to about 2000 mg,
about 1500 mg to about 1750 mg, about 1750 mg to about 3000 mg,
about 1750 mg to about 2750 mg, about 1750 mg to about 2500 mg,
about 1750 mg to about 2250 mg, about 1750 mg to about 2000 mg,
about 2000 mg to about 3000 mg, about 2000 mg to about 2750 mg,
about 2000 mg to about 2500 mg, about 2000 mg to about 2250 mg,
about 2250 mg to about 3000 mg, about 2250 mg to about 2750 mg,
about 2250 mg to about 2500 mg, about 2500 mg to about 3000 mg,
about 2500 mg to about 2750 mg, or about 2750 mg to about 3000
mg.
Kits
Disclosed herein is a kit or pharmaceutical compositions for
treatment of a solid tumor cancer in a subject, e.g., a human
subject, comprising at least one ETBR antagonist in an amount
effective for use in a combination therapy with at least one immune
checkpoint inhibitor, and a pharmaceutically acceptable carrier. In
some embodiments, the at least one ETBR antagonist is at least one
specifically deuterated ETBR antagonist, e.g., deuterated BQ-788 as
described herein. In some embodiments, the at least one ETBR
antagonist, e.g., deuterated BQ-788, is disposed in a single
container with the immune checkpoint inhibitor. In some
embodiments, the at least one ETBR antagonist, e.g., deuterated
BQ-788, is disposed in a first container, and the immune checkpoint
inhibitor is disposed in a second container, wherein the at least
one ETBR antagonist and the immune checkpoint inhibitor are to be
administered approximately contemporaneously.
In some embodiments, the description provides a kit for treatment
of a solid tumor cancer in a human subject, comprising an amount of
at least one immune checkpoint inhibitor, a synergistically
effective amount of BQ-788, and a pharmaceutically acceptable
carrier or excipient. In some embodiments, the BQ-788 is at least
one deuterated BQ-788. In some embodiments, the at least one
checkpoint inhibitor is an anti-PD1 antibody or anti-PD-L1
antibody.
Routes of Administration
Disclosed herein is a variety of routes of administration for the
pharmaceutical compositions disclosed herein. The compounds as
described herein may, in accordance with the disclosure, be
administered in single or divided doses by the oral, parenteral or
topical routes. Administration of the active compound may range
from continuous (intravenous drip) to several oral administrations
per day (for example, Q.O.D. or Q.I.D.) and may include oral,
topical, parenteral, intramuscular, intravenous, sub-cutaneous,
transdermal (which may include a penetration enhancement agent),
buccal, sublingual and suppository administration, among other
routes of administration. Enteric coated oral tablets may also be
used to enhance bioavailability of the compounds from an oral route
of administration. The most effective dosage form will depend upon
the pharmacokinetics of the particular agent(s) chosen as well as
the severity of disease in the patient. Administration of compounds
according to the present disclosure as sprays, mists, or aerosols
for intra-nasal, intra-tracheal or pulmonary administration may
also be used. The present disclosure therefore also is directed to
pharmaceutical compositions comprising an effective amount of
compound as described herein, optionally in combination with a
pharmaceutically acceptable carrier, additive or excipient.
Compounds according to the present disclosure may be administered
in immediate release, intermediate release or sustained or
controlled release forms. In some embodiments, sustained or
controlled release forms are y administered orally, but also in
suppository and transdermal or other topical forms. Intramuscular
injections in liposomal form may also be used to control or sustain
the release of compound at an injection site.
In some embodiments, the pharmaceutical compositions as described
herein is administered orally, parenterally, by inhalation spray,
topically, rectally, nasally, buccally, vaginally or via an
implanted reservoir. The term "parenteral" as used herein includes
subcutaneous, intravenous, intramuscular, intra-articular,
intra-synovial, intrasternal, intrathecal, intrahepatic,
intralesional and intracranial injection or infusion techniques. In
some embodiments, the compositions are administered orally,
intraperitoneally or intravenously.
In some embodiments, sterile injectable forms of the compositions
as described herein are aqueous or oleaginous suspension. These
suspensions may be formulated using suitable dispersing or wetting
agents and suspending agents. The sterile injectable preparation
may also be a sterile injectable solution or suspension in a
non-toxic parenterally-acceptable diluent or solvent, for example
as a solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution and
isotonic sodium chloride solution. In addition, sterile, fixed oils
are conventionally employed as a solvent or suspending medium. For
this purpose, any bland fixed oil may be employed including
synthetic mono- or di-glycerides. Fatty acids, such as oleic acid
and its glyceride derivatives are useful in the preparation of
injectables, as are natural pharmaceutically-acceptable oils, such
as olive oil, castor oil or soybean oil, especially in their
polyoxyethylated versions. These oil solutions or suspensions may
also contain a long-chain alcohol diluent or dispersant, such as
Ph. Helv or similar alcohol.
In some embodiments, the pharmaceutical compositions as described
herein are orally administered in any orally acceptable dosage form
including, but not limited to, capsules, tablets, aqueous
suspensions or solutions. In the case of tablets for oral use,
carriers which are commonly used include lactose and corn starch.
Lubricating agents, such as magnesium stearate, are also typically
added. For oral administration in a capsule form, useful diluents
include lactose and dried corn starch. When aqueous suspensions are
used orally, the active ingredient is combined with emulsifying and
suspending agents. If desired, certain sweetening, flavoring or
coloring agents may also be added.
In some embodiments, the pharmaceutical compositions as described
herein are administered in the form of suppositories for rectal
administration. These can be prepared by mixing the agent with a
suitable non-irritating excipient, which is solid at room
temperature but liquid at rectal temperature and therefore will
melt in the rectum to release the drug. Such materials include
cocoa butter, beeswax and polyethylene glycols.
In some embodiments, the pharmaceutical compositions as described
herein are administered topically. Suitable topical formulations
are readily prepared for each of these areas or organs. Topical
application for the lower intestinal tract can be effected in a
rectal suppository formulation (see above) or in a suitable enema
formulation. Topically-acceptable transdermal patches may also be
used.
In some embodiments, for topical applications, the pharmaceutical
compositions are formulated in a suitable ointment containing the
active component suspended or dissolved in one or more carriers.
Carriers for topical administration of the compounds of this
disclosure include, but are not limited to, mineral oil, liquid
petrolatum, DMSO, white petrolatum, propylene glycol,
polyoxyethylene, polyoxypropylene compound, emulsifying wax and
water. In some embodiments, the compounds may be coated onto a
stent which is to be surgically implanted into a patient in order
to inhibit or reduce the likelihood of occlusion occurring in the
stent in the patient.
In some embodiments, the pharmaceutical compositions are formulated
in a suitable lotion or cream containing the active components
suspended or dissolved in one or more pharmaceutically acceptable
carriers. Suitable carriers include, but are not limited to,
mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters
wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and
water.
In some embodiments, for ophthalmic use, the pharmaceutical
compositions are formulated as micronized suspensions in isotonic,
pH adjusted sterile saline, or as solutions in isotonic, pH
adjusted sterile saline, either with or without a preservative such
as benzylalkonium chloride. Alternatively, for ophthalmic uses, the
pharmaceutical compositions may be formulated in an ointment such
as petrolatum.
In some embodiments, the pharmaceutical compositions as described
herein are administered by nasal aerosol or inhalation. Such
compositions are prepared according to techniques described herein
relating to pharmaceutical compositions and may be prepared as
solutions in saline, employing benzyl alcohol or other suitable
preservatives, absorption promoters to enhance bioavailability,
fluorocarbons, and/or other conventional solubilizing or dispersing
agents. In some embodiments, the description provides formulations
comprising liposomes including an effective amount (e.g., a
synergistically effective amount) of at least one of a ETBR
antagonist or a caspase-8 inhibitor or a combination thereof,
and/or an effective amount (e.g., a synergistically effective
amount) of at least one of an ETAR antagonist, an anti-PD1
antibody, a bRAF inhibitor, niacinamide or a combination thereof,
wherein the liposome formulation is configured or adapted for
intranasal delivery or sublingual delivery. In a further
embodiment, the liposomes further comprise an additional
anti-cancer agent as described above.
In some embodiments, the compositions should be formulated to
contain between about 0.05 milligram to about 750 milligrams or
more, for example about 1 milligram to about 600 milligrams, or
about 10 milligrams to about 500 milligrams of active ingredient,
alone or in combination with at least one other compound according
to the present disclosure. It should also be understood that a
specific dosage and treatment regimen for any particular patient
will depend upon a variety of factors, including the activity of
the specific compound employed, the age, body weight, general
health, sex, diet, time of administration, rate of excretion, drug
combination, and the judgment of the treating physician and the
severity of the particular disease or condition being treated.
In some embodiments, a patient or subject in need of therapy using
compounds according to the methods described herein is treated by
administering to the patient (subject) an effective amount of the
compound according to the present disclosure including
pharmaceutically acceptable salts, solvates or polymorphs thereof
optionally in a pharmaceutically acceptable carrier or diluent,
either alone, or in combination with other known erythopoiesis
stimulating agents as otherwise identified herein.
In some embodiments, the compounds or compositions herein are
administered orally, parenterally, intradermally, by an injection
(intravenously, subcutaneously, or intramuscularly), topically,
including transdermally, in liquid, cream, gel, or solid form, or
by aerosol form.
In some embodiments, the active ingredients are included in the
pharmaceutically acceptable carrier or diluent in an amount
sufficient to deliver to a patient a therapeutically effective
amount for the desired indication, without causing serious toxic
effects in the patient treated. An exemplary dose of the active
compound for all of the herein-mentioned conditions is in the range
from about 10 ng/kg to 300 ng/kg, about 10 ng/kg to 1 .mu.g/kg,
about 1 .mu.g/kg to 10 .mu.g/kg, about 10 .mu.g/kg to 100 .mu.g/kg,
about 100 .mu.g/kg to 1000 .mu.g/kg, about 1 mg/kg to 30 mg/kg,
about 1 mg/kg to 300 mg/kg, or 0.1 to 100 mg/kg per day, more
generally 0.5 to about 25 mg per kilogram body weight of the
recipient/patient per day. A typical topical dosage will range from
0.01-5% wt/wt in a suitable carrier.
In some embodiments, the active ingredient herein is conveniently
administered in any suitable unit dosage form, including but not
limited to, one containing less than 1 mg, 1 mg to 3000 mg, for
example 5 to 500 mg of active ingredient per unit dosage form. An
oral dosage of about 25-250 mg is often convenient.
In some embodiments, the active ingredient is administered to
achieve peak plasma concentrations of the active compound of about
0.00001-30 mM, for example about 0.1-30 M. This may be achieved,
for example, by the intravenous injection of a solution or
formulation of the active ingredient, optionally in saline, or an
aqueous medium or administered as a bolus of the active ingredient.
Oral administration is also appropriate to generate effective
plasma concentrations of active agent.
Methods for Treatment
Disclosed herein are methods for treating or ameliorating a
disease, disorder or symptom thereof in a subject or a patient,
e.g., an animal such as a human, comprising administering to a
subject in need thereof an effective amount, e.g., a
therapeutically effective amount or a synergistically effective
amount, of a pharmaceutical composition as described herein,
wherein the composition is effective for treating or ameliorating
the disease or disorder or symptom thereof in the subject. In some
embodiments, the disease or disorder is an ETBR-related cancer or a
cancer that is insensitive to immune based therapy or both. In some
embodiments, the pharmaceutical composition comprises an effective
amount of a specifically deuterated ETBR antagonist, e.g.,
deuterated BQ-788 or BQ-788-B, as described herein. In some
embodiments, the ETBR-related cancer is at least one of breast
cancer, metastatic breast cancer, melanoma, squamous cell
carcinoma, glioblastoma or a combination thereof. In some
embodiments, the cancer is a solid tumor cancer. In some
embodiments, the ETBR-related cancer to be treated does not include
breast cancer, melanoma, metastatic breast cancer or metastatic
melanoma.
In some embodiments, the administration of a specifically
deuterated ETBR antagonist alone or in a combination with
administration of at least one ETBR antagonist and an immune
checkpoint inhibitor is sufficient to effectuate the treatment or
amelioration of at least one symptom of cancer. In some
embodiments, administration of the ETBR antagonist alone or in a
combination with immune checkpoint inhibitor effectuates
stimulation or enhancement of tumor infiltrating lymphocytes,
macrophages, tertiary lymphoid organ formation or a combination
thereof. In some embodiments, treatment or amelioration of cancer
or stimulation or enhancement of tumor infiltrating lymphocytes,
macrophages, induce tertiary lymphoid organ formation or a
combination thereof, as determined using a V600E+ SM1 cancer model
in mice, e.g., C57BL/6 mouse model. In some embodiments, the at
least one ETBR antagonist and immune checkpoint inhibitor (whether
in single formulation or separate) are administered in unit dosage
forms. In some embodiments, the unit dosage form or forms comprises
a synergistically effective amount of each of the at least one ETBR
antagonist, and the immune checkpoint inhibitor.
In some embodiments, the description provides methods for treating
cancer in a subject, e.g., a solid tumor cancer, comprising
administering to a subject in need thereof an effective dose of a
specifically deuterated ETBR antagonist as described herein alone
or in a combination with an immune checkpoint inhibitor, wherein
the administering effectuates the treatment or amelioration of at
least one symptom of the cancer.
In some embodiments, the description provides methods of treating
cancer in a subject comprising administering to a subject in need
thereof an effective dose of a specifically deuterated ETBR
antagonist as described herein, and administering to the subject an
immune checkpoint inhibitor, wherein the administrations effectuate
at least one of: a. enhancement or stimulation of tumor
infiltrating lymphocytes (TILs), b. increased tumor associated
macrophages (TAMs), c. enhancement or stimulation of tertiary
lymphoid organ (TLO) formation or d. a combination thereof, and
thereby treating or ameliorating at least one symptom of the
cancer. In some embodiments, (a)-(d) are determined in a human by
biopsy or in an animal model. In some embodiments, the animal model
is a V600E+ SM1 cancer model in mice, e.g., C57BL/6 mouse
model.
In some embodiments, the at least one specifically deuterated ETBR
antagonist is at least one deuterated form of BQ-788 as described
herein. In further embodiments, the deuterated BQ-788 is BQ-788-A,
BQ-788-B, BQ-788-C or a combination thereof.
In some embodiments, a method for treating cancer herein comprises
administering to a patient in need thereof at least one ETBR
antagonist, wherein the at least one ETBR antagonist is effective
in treating or ameliorating at least one symptom of the cancer in
the patient. In some embodiments, the at least one ETBR antagonist
is at least one specifically deuterated ETBR antagonist. In some
embodiments, the method comprises administering an effective amount
of the at least one specifically deuterated ETBR antagonist as
described herein, e.g., a deuterated form of BQ-788. In some
embodiments, the deuterated BQ-788 is at least one of BQ-788-A,
BQ-788-B, or BQ-788-C. In some embodiments, the cancer is an
ETBR-related cancer, e.g., an ETBR-related solid tumor cancer. In
some embodiments, the ETBR-related cancer is at least one of breast
cancer, melanoma, squamous cell carcinoma, glioblastoma, ovarian
cancer, pancreatic cancer or a combination thereof. In some
embodiments, the cancer is a solid tumor cancer. In further
embodiments, the cancer is not breast cancer, melanoma, metastatic
breast cancer or metastatic melanoma.
In some embodiments, the method comprises administering a
composition comprising an effective amount of at least one ETBR
antagonist, e.g., at least one specifically deuterated ETBR
antagonist as described herein, and a pharmaceutically acceptable
carrier or excipient as described herein. In some embodiments, the
composition is administered in unit dosage form.
In some embodiments, the method further comprises administering an
additional anti-oncologic agent in combination with, e.g., either
in the same or separate formulations, a specifically deuterated
ETBR antagonist such as a deuterated BQ-788, as described herein.
In some embodiments, the anti-oncologic agent is an anti-PD1
antibody or anti-PD-L1 antibody. In some embodiments, the
anti-oncologic agent, e.g., anti-PD1 or anti-PD-L1 antibody is
administered as a composition comprising a pharmaceutically
acceptable carrier or excipient.
In some embodiments, the method comprises administering a
combination comprising at least one specifically deuterated ETBR
antagonist as described herein, and at least one additional
anti-oncologic agent as described herein. In some embodiments, the
combination comprises a pharmaceutically acceptable carrier or
excipient. In some embodiments, the combination comprises an
effective amount of at least one specifically deuterated ETBR
antagonist, e.g., a deuterated BQ-788, as described herein. In some
embodiments, the combination comprises an amount of an immune
checkpoint inhibitor and a synergistically effective amount of the
at least one specifically deuterated ETBR antagonist, such as a
deuterated BQ-788. In some embodiments, the immune checkpoint
inhibitor is an anti-PD1 antibody.
In some embodiments, the combination comprises an effective amount
of a specifically deuterated ETBR antagonist as described herein,
and a synergistically effective amount of the at least one
anti-oncologic agent. In some embodiments, the combination includes
a pharmaceutical acceptable carrier. In some embodiments, the
combination is comprised within one or more unit dosage forms. In
further embodiments, the combination is administered in separate
unit dosage forms, for example, a first container comprising the at
least one ETBR antagonist, and a second container comprising the at
least one anti-oncologic agent, such as an immune checkpoint
inhibitor. In some embodiments, the specifically deuterated ETBR
antagonist is a deuterated BQ-788 as described herein.
In some embodiments, the pharmaceutical compositions are delivered
intravenously, intramuscularly, subcutaneously, orally,
intranasally, sublingually, transdermally, topically,
intraperitoneally, parenterally, intranasally, or
intracranially.
In some embodiments, the ETBR-antagonist, e.g., deuterated
ETBR-antagonist or deuterated BQ-788, is administered in the form
of a liposomal formulation as described herein.
In some embodiments, a method for treating ETBR-related metastatic
brain cancer is provided. The method comprises administering an
effective amount to a subject in need thereof a pharmaceutical
composition of the present disclosure, wherein the pharmaceutical
composition is effective for treating or ameliorating a symptom of
ETBR-related metastatic brain cancer. In some embodiments, the
ETBR-related metastatic brain cancer is metastatic melanoma-related
brain cancer, metastatic squamous cell carcinoma-related brain
cancer, glioblastoma or a combination thereof. In some embodiments,
the composition comprises an effective amount of a specifically
deuterated ETBR antagonist, e.g., a deuterated BQ-788 as described
herein, and a pharmaceutically acceptable carrier.
In some embodiments, the description provides methods for treating
a solid tumor cancer in a human subject, comprising administering
effective doses of an ETBR antagonist and further administering an
immune checkpoint inhibitor to the subject in need thereof, wherein
the administration of the ETBR antagonist and immune checkpoint
inhibitor effectuates at least one of: (i) enhancement or
stimulation of tumor infiltrating lymphocytes (TILs), (ii)
increased tumor associated macrophages (TAMs), (iii) enhancement or
stimulation of tertiary lymphoid organ (TLO) formation or (iv) a
combination thereof, wherein the ETBR antagonist and immune
checkpoint inhibitor effectuate the treatment or alleviation of at
least one symptom of the solid tumor cancer. In some embodiments,
the formation of (i)-(iv) is performed in a mouse model. In some
embodiments, the mouse model is the V600E+ SM1 cancer model in
C57BL/6 mice. In some embodiments, the immune checkpoint inhibitor
is an anti-PD1 or anti-PD-L1 antibody. In some embodiments, the
effective dose is a synergistically effective amount, e.g., from
0.1 .mu.g to 5000 mg. In some embodiments, the specifically
deuterated ETBR antagonist is a deuterated BQ-788. In some
embodiments, the deuterated BQ-788 is BQ-788-B. In some
embodiments, the specifically deuterated ETBR antagonist, e.g.,
deuterated BQ-788, includes a pharmaceutically acceptable carrier
or excipient. In some embodiments, the ETBR antagonist (e.g.,
deuterated ETBR such as deuterated BQ-788) and immune checkpoint
inhibitor are administered separately. In some embodiments, the
ETBR antagonist (e.g., deuterated ETBR such as deuterated BQ-788)
and immune checkpoint inhibitor are administered in the same
formulation.
In some embodiments, the description provides a method of treating
an ETBR-related solid tumor cancer in a subject comprising
administering to a subject in need thereof, e.g., a human, at least
one deuterated BQ-788 at an effective amount or synergistically
effective amount with an immune checkpoint inhibitor, and a
pharmaceutically acceptable carrier or excipient, wherein the
deuterated BQ-788 and immune checkpoint inhibitor effectuate the
treatment or amelioration of at least one symptom of the
ETBR-related solid tumor cancer in the subject. In some
embodiments, the deuterated BQ-788 is administered as a liposomal
formulation.
In some embodiments, the immune based therapy includes at least one
of an immune checkpoint inhibitor (e.g., an anti-PD-1 antibody), a
cancer vaccine, a Chimeric Antigen Receptor T-Cell (CAR-T) therapy
or a combination thereof.
In some embodiments, the description provides a method of
inhibiting melanoma invasion and metastasis in a patient comprising
administering to a subject in need thereof an effective amount,
e.g., a therapeutically effective amount or a synergistically
effective amount, of a pharmaceutical composition as described
herein, wherein the composition is effective for inhibiting
melanoma invasion and metastasis.
In some embodiments, the description provides a method of inducing
melanoma cell death (apoptosis) comprising administering to a
subject in need thereof an effective amount, e.g., a
therapeutically effective amount or a synergistically effective
amount, of a pharmaceutical composition as described herein,
wherein the composition is effective for inducing melanoma cell
death.
In some embodiments, the description provides a method of
inhibiting blood supply to melanoma tumors in a patient comprising
administering to a subject in need thereof an effective amount,
e.g., a therapeutically effective amount or a synergistically
effective amount, of a pharmaceutical composition as described
herein, wherein the composition is effective for inhibiting blood
supply to melanoma tumors.
In some embodiments, the pharmaceutical composition comprises about
1% to about 95% of the active ingredient, single-dose forms of
administration comprising about 20% to about 90% of the active
ingredient and administration forms which are not single-dose
comprising about 5% to about 20% of the active ingredient. Unit
dose forms are, for example, coated tablets, tablets, ampoules,
vials, suppositories or capsules. Other forms of administration
are, for example, ointments, creams, pastes, foams, tinctures,
lipsticks, drops, sprays, dispersions and the like. Examples are
capsules containing from about 0.05 g to about 1.0 g of the active
ingredient.
In some embodiments, the active ingredient is included in the
pharmaceutically acceptable carrier or diluent in an amount
sufficient to deliver to a patient a therapeutically effective
amount for the desired indication, without causing serious toxic
effects in the patient treated. An exemplary dose of the active
compound for all of the herein-mentioned conditions is in the range
from about 10 ng/kg to 300 mg/kg, for example 0.1 to 100 mg/kg per
day, more generally 0.5 to about 25 mg per kilogram body weight of
the recipient/patient per day. A typical topical dosage will range
from 0.01-5% wt/wt in a suitable carrier. The compound is
conveniently administered in any suitable unit dosage form,
including but not limited to one containing less than 1 mg, 1 mg to
3000 mg, for example 5 to 500 mg of active ingredient per unit
dosage form. An oral dosage of about 25-250 mg is often convenient.
In some embodiments, the active ingredient is administered to
achieve peak plasma concentrations of the active compound of about
0.00001-30 mM, for example about 0.1-30 M.
Dosage Regimen
Disclosed herein is a treatment regimen. In some embodiments, the
treatment regimen includes a dosage pharmaceutical composition with
about 100 .mu.g to about 4000 .mu.g of each included active
ingredient (i.e., at least one specifically deuterated ETBR
antagonist as described herein, the ETAR antagonist, the anti-PD1
antibody, the bRAF inhibitor, the niacinamide, or the caspase-8
inhibitor). The dosage can be a sustained release dosage in which
about 50 .mu.g to about 3000 .mu.g of each of the active
ingredients is an initial burst, while about 50 .mu.g to about 3000
.mu.g of the each of the active ingredients is a sustained release
over 2 hours.
In some embodiments, each of the active ingredient of a
pharmaceutical composition of the present disclosure can be present
in any of the dosage formulation (e.g., initial burst, sustained
release dosage, etc.) in about 100 .mu.g to about 4000 .mu.g, about
100 .mu.g to about 3750 .mu.g, about 100 .mu.g to about 3500 .mu.g,
about 100 .mu.g to about 3250 .mu.g, about 100 .mu.g to about 3000
.mu.g, about 100 .mu.g to about 2750 .mu.g, about 100 .mu.g to
about 2500 .mu.g, about 100 .mu.g to about 2250 .mu.g, about 100
.mu.g to about 2000 .mu.g, about 100 .mu.g to about 1750 .mu.g,
about 100 .mu.g to about 1500 .mu.g, about 100 .mu.g to about 1250
.mu.g, about 100 .mu.g to about 1000 .mu.g, about 100 .mu.g to
about 750 .mu.g, about 100 .mu.g to about 500 .mu.g, about 250
.mu.g to about 4000 .mu.g, about 250 .mu.g to about 3750 .mu.g,
about 250 .mu.g to about 3500 Gg, about 250 .mu.g to about 3250
.mu.g, about 250 .mu.g to about 3000 .mu.g, about 250 .mu.g to
about 2750 .mu.g, about 250 .mu.g to about 2500 .mu.g, about 250
.mu.g to about 2250 .mu.g, about 250 .mu.g to about 2000 .mu.g,
about 250 .mu.g to about 1750 .mu.g, about 250 .mu.g to about 1500
.mu.g, about 250 .mu.g to about 1250 .mu.g, about 250 .mu.g to
about 1000 .mu.g, about 250 .mu.g to about 750 .mu.g, about 250
.mu.g to about 500 .mu.g, about 500 .mu.g to about 4000 .mu.g,
about 500 .mu.g to about 3750 .mu.g, about 500 .mu.g to about 3500
.mu.g, about 500 g to about 3250 .mu.g, about 500 .mu.g to about
3000 .mu.g, about 500 .mu.g to about 2750 .mu.g, about 500 .mu.g to
about 2500 .mu.g, about 500 .mu.g to about 2250 .mu.g, about 500
.mu.g to about 2000 .mu.g, about 500 .mu.g to about 1750 .mu.g,
about 500 .mu.g to about 1500 .mu.g, about 500 .mu.g to about 1250
.mu.g, about 500 .mu.g to about 1000 .mu.g, about 500 .mu.g to
about 750 .mu.g, about 750 .mu.g to about 4000 .mu.g, about 750
.mu.g to about 3750 .mu.g, about 750 .mu.g to about 3500 .mu.g,
about 750 .mu.g to about 3250 .mu.g, about 750 .mu.g to about 3000
.mu.g, about 750 .mu.g to about 2750 .mu.g, about 750 .mu.g to
about 2500 .mu.g, about 750 .mu.g to about 2250 .mu.g, about 750
.mu.g to about 2000 .mu.g, about 750 .mu.g to about 1750 .mu.g,
about 750 .mu.g to about 1500 .mu.g, about 750 .mu.g to about 1250
.mu.g, about 750 .mu.g to about 1000 .mu.g, about 1000 .mu.g to
about 4000 .mu.g, about 1000 .mu.g to about 3750 .mu.g, about 1000
.mu.g to about 3500 .mu.g, about 1000 .mu.g to about 3250 .mu.g,
about 1000 .mu.g to about 3000 .mu.g, about 1000 .mu.g to about
2750 .mu.g, about 1000 .mu.g to about 2500 .mu.g, about 1000 .mu.g
to about 2250 .mu.g, about 1000 .mu.g to about 2000 .mu.g, about
1000 .mu.g to about 1750 .mu.g, about 1000 .mu.g to about 1500
.mu.g, about 1000 .mu.g to about 1250 .mu.g, about 1250 .mu.g to
about 4000 .mu.g, about 1250 .mu.g to about 3750 .mu.g, about 1250
.mu.g to about 3500 .mu.g, about 1250 .mu.g to about 3250 .mu.g,
about 1250 .mu.g to about 3000 .mu.g, about 1250 .mu.g to about
2750 .mu.g, about 1250 .mu.g to about 2500 .mu.g, about 1250 .mu.g
to about 2250 .mu.g, about 1250 .mu.g to about 2000 .mu.g, about
1250 .mu.g to about 1750 .mu.g, about 1250 .mu.g to about 1500
.mu.g, about 1500 .mu.g to about 4000 .mu.g, about 1500 .mu.g to
about 3750 .mu.g, about 1500 .mu.g to about 3500 .mu.g, about 1500
.mu.g to about 3250 .mu.g, about 1500 .mu.g to about 3000 .mu.g,
about 1500 .mu.g to about 2750 .mu.g, about 1500 .mu.g to about
2500 .mu.g, about 1500 .mu.g to about 2250 .mu.g, about 1500 .mu.g
to about 2000 .mu.g, about 1500 .mu.g to about 1750 .mu.g, about
1750 .mu.g to about 4000 .mu.g, about 1750 .mu.g to about 3750
.mu.g, about 1750 .mu.g to about 3500 .mu.g, about 1750 .mu.g to
about 3250 .mu.g, about 1750 .mu.g to about 3000 .mu.g, about 1750
.mu.g to about 2750 .mu.g, about 1750 .mu.g to about 2500 .mu.g,
about 1750 .mu.g to about 2250 .mu.g, about 1750 .mu.g to about
2000 .mu.g, about 2000 .mu.g to about 4000 .mu.g, about 2000 .mu.g
to about 3750 .mu.g, about 2000 .mu.g to about 3500 .mu.g, about
2000 .mu.g to about 3250 .mu.g, about 2000 .mu.g to about 3000
.mu.g, about 2000 .mu.g to about 2750 .mu.g, about 2000 .mu.g to
about 2500 .mu.g, about 2000 .mu.g to about 2250 .mu.g, about 2250
.mu.g to about 4000 .mu.g, about 2250 .mu.g to about 3750 .mu.g,
about 2250 .mu.g to about 3500 .mu.g, about 2250 .mu.g to about
3250 .mu.g, about 2250 .mu.g to about 3000 .mu.g, about 2250 .mu.g
to about 2750 .mu.g, about 2250 .mu.g to about 2500 .mu.g, about
2500 .mu.g to about 4000 .mu.g, about 2500 .mu.g to about 3750
.mu.g, about 2500 .mu.g to about 3500 .mu.g, about 2500 .mu.g to
about 3250 .mu.g, about 2500 .mu.g to about 3000 .mu.g, about 2500
.mu.g to about 2750 .mu.g, about 2750 .mu.g to about 4000 .mu.g,
about 2750 .mu.g to about 3750 .mu.g, about 2750 .mu.g to about
3500 .mu.g, about 2750 .mu.g to about 3250 .mu.g, about 2750 .mu.g
to about 3000 .mu.g, about 3000 .mu.g to about 4000 .mu.g, about
3000 .mu.g to about 3750 .mu.g, about 3000 .mu.g to about 3500
.mu.g, about 3000 .mu.g to about 3250 .mu.g, about 3250 .mu.g to
about 4000 .mu.g, about 3250 .mu.g to about 3750 .mu.g, about 3250
.mu.g to about 3500 .mu.g, about 3500 .mu.g to about 4000 .mu.g,
about 3500 .mu.g to about 3750 .mu.g, or about 3750 .mu.g to about
4000 .mu.g.
In some embodiments, each active ingredient of a pharmaceutical
composition of the present disclosure is present in about 0.1 mg/mL
to about 50 mg/mL, about 0.1 mg/mL to about 25 mg/mL, about 0.1
mg/mL to about 10 mg/mL, about 1 mg/mL to about 50 mg/mL, about 1
mg/mL to about 25 mg/mL, about 1 mg/mL to about 10 mg/mL, about 0.1
mg/mL to about 5.0 mg/mL (e.g., about 0.1 mg/mL to about 4.5 mg/mL,
about 0.1 mg/mL to about 4.0 mg/mL, about 0.1 mg/mL to about 3.5
mg/mL, about 0.1 mg/mL to about 3.0 mg/mL, about 0.1 mg/mL to about
2.5 mg/mL, about 0.1 mg/mL to about 2.0 mg/mL, about 0.1 mg/mL to
about 1.5 mg/mL, about 0.1 mg/mL to about 1.0 mg/mL, about 0.1
mg/mL to about 0.5 mg/mL, about 0.5 mg/mL to about 4.5 mg/mL, about
0.5 mg/mL to about 4.0 mg/mL, about 0.5 mg/mL to about 3.5 mg/mL,
about 0.5 mg/mL to about 3.0 mg/mL, about 0.5 mg/mL to about 2.5
mg/mL, about 0.5 mg/mL to about 2.0 mg/mL, about 0.5 mg/mL to about
1.5 mg/mL, about 0.5 mg/mL to about 1.0 mg/mL, about 1.0 mg/mL to
about 4.5 mg/mL, about 1.0 mg/mL to about 4.0 mg/mL, about 1.0
mg/mL to about 3.5 mg/mL, about 1.0 mg/mL to about 3.0 mg/mL, about
1.0 mg/mL to about 2.5 mg/mL, about 1.0 mg/mL to about 2.0 mg/mL,
about 1.0 mg/mL to about 1.5 mg/mL, about 1.5 mg/mL to about 4.5
mg/mL, about 1.5 mg/mL to about 4.0 mg/mL, about 1.5 mg/mL to about
3.5 mg/mL, about 1.5 mg/mL to about 3.0 mg/mL, about 1.5 mg/mL to
about 2.5 mg/mL, about 1.5 mg/mL to about 2.0 mg/mL, about 2.0
mg/mL to about 4.5 mg/mL, about 2.0 mg/mL to about 4.0 mg/mL, about
2.0 mg/mL to about 3.5 mg/mL, about 2.0 mg/mL to about 3.0 mg/mL,
about 2.0 mg/mL to about 2.5 mg/mL, about 2.5 mg/mL to about 4.5
mg/mL, about 2.5 mg/mL to about 4.0 mg/mL, about 2.5 mg/mL to about
3.5 mg/mL, about 2.5 mg/mL to about 3.0 mg/mL, about 3.0 mg/mL to
about 4.5 mg/mL, about 3.0 mg/mL to about 4.0 mg/mL, about 3.0
mg/mL to about 3.5 mg/mL, about 3.5 mg/mL to about 4.5 mg/mL, about
3.5 mg/mL to about 4.0 mg/mL, or about 3.5 mg/mL to about 4.5
mg/mL, relative to the pharmaceutical composition).
In some embodiments, each active ingredient of a pharmaceutical
composition of the present disclosure is present in about 0.1
.mu.g/mL to about 50 .mu.g/mL, about 0.1 .mu.g/mL to about 25 g/mL,
about 0.1 .mu.g/mL to about 10 .mu.g/mL, about 1 .mu.g/mL to about
50 .mu.g/mL, about 1 .mu.g/mL to about 25 .mu.g/mL, about 1
.mu.g/mL to about 10 .mu.g/mL, about 0.1 .mu.g/mL to about 5.0
.mu.g/mL, e.g., about 1 .mu.g/mL to about 5 g/mL, about 0.1
.mu.g/mL to about 4.0 .mu.g/mL, about 0.1 .mu.g/mL to about 3.5
g/mL, about 0.1 .mu.g/mL to about 3.0 .mu.g/mL, about 0.1 .mu.g/mL
to about 2.5 .mu.g/mL, about 0.1 .mu.g/mL to about 2.0 .mu.g/mL,
about 0.1 .mu.g/mL to about 1.5 .mu.g/mL, about 0.1 .mu.g/mL to
about 1.0 .mu.g/mL, about 0.1 .mu.g/mL to about 0.5 .mu.g/mL, about
0.5 .mu.g/mL to about 4.5 .mu.g/mL, about 0.5 .mu.g/mL to about 4.0
.mu.g/mL, about 0.5 .mu.g/mL to about 3.5 .mu.g/mL, about 0.5
.mu.g/mL to about 3.0 .mu.g/mL, about 0.5 .mu.g/mL to about 2.5
.mu.g/mL, about 0.5 .mu.g/mL to about 2.0 .mu.g/mL, about 0.5
.mu.g/mL to about 1.5 g/mL, about 0.5 .mu.g/mL to about 1.0
.mu.g/mL, about 1.0 .mu.g/mL to about 4.5 .mu.g/mL, about 1.0
.mu.g/mL to about 4.0 .mu.g/mL, about 1.0 .mu.g/mL to about 3.5
.mu.g/mL, about 1.0 .mu.g/mL to about 3.0 .mu.g/mL, about 1.0
.mu.g/mL to about 2.5 .mu.g/mL, about 1.0 .mu.g/mL to about 2.0
.mu.g/mL, about 1.0 .mu.g/mL to about 1.5 .mu.g/mL, about 1.5
.mu.g/mL to about 4.5 .mu.g/mL, about 1.5 .mu.g/mL to about 4.0
.mu.g/mL, about 1.5 .mu.g/mL to about 3.5 .mu.g/mL, about 1.5
.mu.g/mL to about 3.0 .mu.g/mL, about 1.5 .mu.g/mL to about 2.5
g/mL, about 1.5 .mu.g/mL to about 2.0 .mu.g/mL, about 2.0 .mu.g/mL
to about 4.5 .mu.g/mL, about 2.0 .mu.g/mL to about 4.0 .mu.g/mL,
about 2.0 .mu.g/mL to about 3.5 .mu.g/mL, about 2.0 .mu.g/mL to
about 3.0 .mu.g/mL, about 2.0 .mu.g/mL to about 2.5 .mu.g/mL, about
2.5 .mu.g/mL to about 4.5 .mu.g/mL, about 2.5 .mu.g/mL to about 4.0
.mu.g/mL, about 2.5 .mu.g/mL to about 3.5 .mu.g/mL, about 2.5
.mu.g/mL to about 3.0 .mu.g/mL, about 3.0 .mu.g/mL to about 4.5
.mu.g/mL, about 3.0 .mu.g/mL to about 4.0 .mu.g/mL, about 3.0
.mu.g/mL to about 3.5 g/mL, about 3.5 .mu.g/mL to about 4.5
.mu.g/mL, about 3.5 .mu.g/mL to about 4.0 .mu.g/mL, or about 3.5
g/mL to about 4.5 .mu.g/mL, relative to the pharmaceutical
composition.
EXAMPLES
Example 1. Synthesis of Deuterated ETBR Antagonists
Deuterated ETBR antagonists may be prepared by deuterating known
and commercial ETBR antagonists by standard methods and
procedures.
Specific deuterated ETBR antagonists may be prepared by the schemes
presented below. BQ-788-B can be prepared by the method
demonstrated in FIG. 14.
Intermediate 13 of FIG. 14 can be prepared by the following scheme
2 depicted in FIG. 15 (Intermediate 13):
A non-deuterated analog of Intermediate 13 can be prepared by
substituting LiAlH.sub.4 in place of LiAlD.sub.4 in Step 4.
BQ-788-A and BQ-788-C can be prepared by substituting a deuterated
analog of Intermediate 5 in Step 3 of scheme 1. Such an analog can
be prepared by the method demonstrated in FIG. 16 (Intermediate 5d)
below:
Compound 10 from Scheme 3 is then used in place of Compound 5 in
scheme 1. For BQ-788-C Scheme 1 is then followed to completion. For
BQ-788-A, the non-deuterated analog of Intermediate 13 of Scheme 1
is used Intermediate 4 of Scheme 3 can be prepared by reacting a
bromonated indole with NaBD4 in the presence of a palladium
catalyst.
In an exemplary embodiment, compound BQ-788-A can be prepared by
the method demonstrated in FIG. 17.
In addition, compound BQ-788-C can be prepared according to the
method demonstrated in FIG. 18.
The number and position of the deuterium atoms is not to be limited
by the specific schemes or examples shown herein. The preparation
of compounds with more deuterium substitution can be readily
extrapolated from the schemes presented here using commonly known
starting materials or prepared using standard synthetic
methods.
Example 2. Biological Activities of Deuterated ETBR Antagonists
Determination of CXCR4 Inhibitory Effect.
The inhibitory effect on CXCR4 (h) was determined for BQ-788 (FIG.
4A), and BQ-788 (FIG. 4B) BQ-788-B (i.e., "Compound 1"). Cellular
agonist effect was calculated as a % of control response to a known
reference agonist for CXCR4 (h), and cellular antagonist effect was
calculated as a % inhibition of control reference agonist response
for CXCR4. Recombinant human CXCR4 was expressed in CHO cells, and
stimulated with 1 nM SDF-1.alpha. and incubated at 28.degree. C.
Dielectric spectroscopy was used to measure impedance of the cells.
Results showing .gtoreq.50% inhibition of agonist effect are
considered significant while those showing less than 25% inhibition
are not considered significant. The IC50 for BQ-788 was greater
than about 1.0E-6 M. The IC50 for BQ-788-B was not calculable.
Determination of ETA (h) Inhibitory Effect for BQ-788 and
BQ-788-B.
FIGS. 5A and 5B demonstrate the determination of ETA (h) inhibitory
effect for, A) BQ-788 and B) BQ-788-B (i.e., "Compound 1").
Cellular agonist effect was calculated as a % of control response
to a known reference agonist for ETA (h), and cellular antagonist
effect was calculated as a % inhibition of control reference
agonist response for ETA. Results showing .gtoreq.50% inhibition of
agonist effect are considered significant while those showing less
than 25% inhibition are not considered significant. The IC50 for
BQ-788 and BQ-788-B was not calculable (i.e., the dose-response
curve shows less than 25% effect at the highest validated testing
concentration).
Determination of ETBR Inhibitory Effect for Specifically Deuterated
ETRB Antagonists.
FIG. 6 demonstrates that specifically deuterated ETRB antagonists
inhibit melanoma growth and metastasis, and induce apoptosis in
melanoma tumor cells. Cellular agonist effect was calculated as a %
of control response to a known reference agonist for ETB (h), and
cellular antagonist effect was calculated as a % inhibition of
control reference agonist response for ETB. Results showing 250%
inhibition of agonist effect are considered significant while those
showing less than 25% inhibition are not considered significant.
The IC50 for a non-deuterated ETRB antagonist was 5.1E08 M and the
Kd was 1.3E-08; while the IC50 for specifically deuterated ETRB
antagonists were 9.6E-08 M and a Kd of 2.5E-08. Surprisingly, in PK
studies in vivo, the specifically deuterated ETRB antagonists
demonstrated enhanced biologic activity relative to the
non-deuterated counterpart.
Plasma Concentrations of BQ-788 Versus BQ-788-B.
FIG. 7 illustrates that BQ-788-B (curve "B"), a deuterated analog
of BQ-788, demonstrates enhanced plasma concentrations relative to
BQ-788. Briefly, rats (N=4 animals per timepoint) were administered
either BQ-788 or the deuterated form, BQ-788-B at a dose of 250
.mu.g/kg via IV infusion. Plasma samples were collected at various
time points and ET-1 ELISA performed. BQ788 and BQ788-B are peptide
drugs that are rapidly degraded in plasma and thus drug levels are
difficult to detect directly. However, when BQ788 binds ETBR, this
results in an increase in plasma concentrations of ET-1, the ligand
for ETBR. As such, plasma levels of ET-1 are commonly used as an
indirect measure of BQ-788 biologic activity. Significantly, the
deuterated compound BQ-788-B demonstrates an enhanced duration and
amplitude of response relative to the undeuterated form as
exemplified by the prolonged peak out to about 3 hours as compared
to BQ-788, which demonstrates a transient peak at about 30 minutes.
The IC50 for BQ-788-B is 9.6E-08 M (MW=665.37). The IC50 for BQ-788
is 5.6E-08 (MW=663.78).
BQ-788-B in Combination with Anti-PD1 Demonstrates Synergistic
Results.
Dual combination of specifically deuterated compounds and
immunotherapeutics (FIG. 8), result in superior efficacy relative
combinations with approved cancer drugs. The syngenic melanoma
model V600E+(BRAF mutated) SM1 tumor model was used in C57BL/6 mice
to assess efficacy of deuterated ETRB antagonists in combination
with immunotherapeutics ("B+P") as compared to a standard
treatment, dabrafenib with anti-PD1 ("D+P"). Previous studies have
indicated that V600E+ model demonstrates no efficacy for anti-PD1
as a single agent (and little tumor infiltrating lymphocytes
(TILs)). In this study 6-8 week old female C57BL/6 mice were
inoculated with SM1 tumor fragments (TME*components present).
Dosing was initiated when tumors were 150 mm3. The general dosing
schemes were as follows: dabrafenib (30 mg/kg daily by oral
gavage), immunotherapeutic 10 mg/kg Q4D IP beginning 2 days after
dabrafenib), deuterated ETRB antagonist (4 .mu.g administered QOD
IV beginning 2 days after dabrafenib). Tumors were measured three
times per week, and the study was terminated after 21 days of
dosing and IHC analysis of tumors was performed. The dual
combination of the immunotherapeutic and the deuterated ETRB
antagonist induced tumor shrinkage below baseline. In stark
contrast, a standard combination of dabrafenib and the
immunotherapeutic failed to shrink tumors but demonstrated
intermediate tumor growth inhibition. IHC analysis of tumors
treated with immunotherapeutics and deuterated ETRB antagonists
revealed that tumors had been eradicated leaving only residual
adipose tissue. In sum, the combination of immunotherapeutic
compounds with specifically deuterated ETRB antagonists as
described herein provided significant improvement against tumor
growth relative to the existing therapeutic paradigm.
Dual Combination BQ-788-B and Immunocheckpoint Inhibitors
Eradicates Tumors.
FIG. 9 demonstrates the results of histological examination of
V600E+ melanoma tumor cells implanted into C57BL/6 mice 21 days
after treatment as indicated in FIG. 8. The specifically deuterated
compound BQ-788-B and immunocheckpoint inhibitors (e.g. anti-PD1,
anti-PD1, anti-CTLA) combination therapy eradicated the tumors in
21 days, promoted robust infiltration by CD8+ lymphocytes (TILs),
and tertiary lymphoid organ (TLO) formation. TIL infiltration is
exemplified by the dark punctuate staining. TLOs are functionally
equivalent to lymph nodes, produce tumor-specific T-and B-cells,
and induce long lasting anti-tumor immunity.
Intratumoral TLO Formation Induced by Combination Therapy Including
Anti-PD1 and BQ-788-B.
FIG. 10 demonstrates the histological examination of V600E+
melanoma tumor cells implanted into C57BL/6 mice 21 days after
treatment as indicated in FIG. 8 with BQ-788-B and anti-PD1
combination therapy. The staining of CD8+, CD4+ and Treg (FoxP3)
lymphocytes (dark punctuate staining) indicates that the
combination therapy promotes strong mobilization of lymphocytes to
the tumor, which is associated with tumor eradication and positive
patient outcomes.
Intratumoral (Internal) TLO Formation Associated with Treatment
with BQ-788-B.
FIG. 11 provides table summaries of the results obtained with
combination therapies (two- and three-part), TLO formation and
efficacy for tumor eradication. The model system tested is as
described for FIG. 8. The combinations included dabrafenib+anti-PD1
("D+P"); dabrafenib+anti-PD1+BQ-788-B at 0.6 .mu.g ("D+P+B(0.6
.mu.g)"); dabrafenib+anti-PD1+BQ-788-B at 4.0 .mu.g ("D+P+B(4.0
.mu.g)"); dabrafenib+anti-PD1+BQ-788-B at 100 .mu.g ("D+P+B(100
.mu.g)"); and anti-PD1+BQ-788-B at (4.0 .mu.g) ("P+B(4.0 .mu.g)").
The data indicate that (i) internal TLO formation is associated
with tumor eradication; and (ii) the combination of anti-PD1
antibody and BQ-788-B was most frequently associated with
intratumoral TLO formation and tumor reduction. FIG. 12 presents
the efficacy results as a function of tumor volume (mm3). The
inclusion of BQ-788-B with anti-PD1 is synergistic and appears to
help restore sensitivity to anti-PD1. The addition of dabrafenib to
anti-PD1/BQ-788-B combination impairs efficacy, possibly due to
dabrafenib's ability to increase Tregs and tumor-associated
macrophages (TAMs).
BQ-788-B at 0.6 .mu.g in Combination with Immunocheckpoint
Inhibitors and Dabrafenib Promotes Diffuse CD8+ TIL Staining.
FIG. 13 shows demonstrates the histological examination of V600E+
melanoma tumor cells implanted into C57BL/6 mice 21 days after
treatment as indicated in FIG. 8 with the respective combination
therapy. The diffuse distribution of CD8+ TIL staining (dark
punctuate staining) appears to be associated with higher efficacy
as compared to those with peripheral distribution of TILs.
Thus, specifically deuterated forms of BQ-788 as described herein,
e.g., BQ-788-A BQ-788-B, BQ-788-C and others described herein,
demonstrate synergistic activity with anti-oncologic agents in a
preclinical melanoma model in which anti-PD1 lacks any efficacy as
a single agent. Tumor reduction or eradication correlates well with
intratumoral TLO formation or neogenesis, and diffuse infiltration
pattern of TILs rather than tumor-peripheral TIL distribution. TLO
neogenesis has prognostic implications and correlates will with
increased patient survival. The dual combination of specifically
deuterated ETBR antagonists and anti-oncologic agents is superior
to other dual and triple combinations in terms of (i) anti-tumor
efficacy; (ii) low anticipated toxicity (based upon established
safety profile of parent compound in humans); and (iii) overall
treatment cost (relative to triple therapies). In addition, IV
administration allows for a 2-3 order of magnitude dose reduction
relative to IP or PO administration (e.g. typical doses of 200-600
.mu.g BQ788 vs. 0.6-4.0 .mu.g deuterated BQ-788).
Example 3. Treatment of Melanoma in a Human Subject
A human patient suffering melanoma, e.g., malignant melanoma or
metastatic melanoma, is administered compounds or pharmaceutical
compositions according to a method for treatment disclosed herein.
The treatment cures the patient or ameliorates the patient's one or
more symptoms such as a sore, spread of pigment from the border of
a spot into surrounding skin, redness or a new swelling beyond the
border of the mole, change in sensation, such as itchiness,
tenderness, or pain, or change in the surface of a mole--scaliness,
oozing, bleeding, or the appearance of a lump or bump.
Example 4. Treatment of a Malignant Solid Tumor in a Human
Subject
A human patient suffering a malignant solid tumor, e.g., pancreatic
tumor, ovarian tumor, sarcomas, carcinomas, and lymphomas, is
administered compounds or pharmaceutical compositions according to
a method for treatment disclosed herein. The treatment reduces a
tumor volume or mass, or eradicates the tumor in the patient.
Example 5. Treatment of a Pancreatic Cancer in a Human Subject
A human patient suffering a pancreatic cancer is administered
compounds or pharmaceutical compositions according to a method for
treatment disclosed herein. The treatment cures the patient or
ameliorates the patient's one or more symptoms such as Jaundice,
light-colored stools, dark urine, pain in the upper or middle
abdomen and back, weight loss, appetite loss, or fatigue.
Example 6. Treatment of an Ovarian Cancer in a Human Subject
A human patient suffering an ovarian cancer is administered
compounds or pharmaceutical compositions according to a method for
treatment disclosed herein. The treatment cures the patient or
ameliorates the patient's one or more symptoms for example:
abdominal bloating, indigestion or nausea, changes in appetite such
as a loss of appetite or feeling full sooner, pressure in the
pelvis or lower back, a frequent or urgent need to urinate and/or
constipation, changes in bowel movements, increased abdominal
girth, tiredness or low energy, or changes in menstruation.
Example 7. Treatment of Squamous Cell Carcinoma in a Human
Subject
A human patient suffering squamous cell carcinoma is administered
compounds or pharmaceutical compositions according to a method for
treatment disclosed herein. The treatment cures the patient or
ameliorates the patient's one or more symptoms such as firm red
nodule, flat sore with a scaly crust, new sore or raised area on an
old scar or ulcer, rough scaly path on a lip or inside a mouth,
scaly red patches, open sores, or warts or elevated growths with a
central depression on or in anus on genitals.
Example 8. Treatment of Glioblastoma in a Human Subject
A human patient suffering glioblastoma is administered compounds or
pharmaceutical compositions according to a method for treatment
disclosed herein. The treatment cures the patient, reduces or
eradicates brain tumor, or ameliorates the patient's one or more
symptoms such as headache, nausea, vomiting, memory loss,
drowsiness, blurred vision, change to personality, mood, or
concentration, localized neurological problems, or seizure.
While some embodiments of the present invention have been shown and
described herein, it will be obvious to those skilled in the art
that such embodiments are provided by way of example only. Numerous
variations, changes, and substitutions will now occur to those
skilled in the art without departing from the invention. It should
be understood that various alternatives to the embodiments of the
invention described herein may be employed in practicing the
invention. It is intended that the following claims define the
scope of the invention and that methods and structures within the
scope of these claims and their equivalents be covered thereby.
SEQUENCE LISTINGS
1
1120PRTArtificial
SequenceSyntheticMISC_FEATURE(1)..(1)AcetylationMISC_FEATURE(20)..(20)Car-
boxylation 1Ala Ala Val Ala Leu Leu Pro Ala Val Leu Leu Ala Ala Leu
Ala Pro1 5 10 15Ile Glu Thr Asp 20
* * * * *
References